WO2018060212A1 - Mélanges et préparations comportant un sel d'edta de type alkylammonium - Google Patents

Mélanges et préparations comportant un sel d'edta de type alkylammonium Download PDF

Info

Publication number
WO2018060212A1
WO2018060212A1 PCT/EP2017/074418 EP2017074418W WO2018060212A1 WO 2018060212 A1 WO2018060212 A1 WO 2018060212A1 EP 2017074418 W EP2017074418 W EP 2017074418W WO 2018060212 A1 WO2018060212 A1 WO 2018060212A1
Authority
WO
WIPO (PCT)
Prior art keywords
formulation
edta
lipid
oil
component
Prior art date
Application number
PCT/EP2017/074418
Other languages
English (en)
Inventor
Justas Barauskas
Catalin Nistor
Markus Johnsson
Original Assignee
Camurus Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB1616366.9A external-priority patent/GB201616366D0/en
Priority to RU2019110439A priority Critical patent/RU2775780C2/ru
Priority to EP17772707.0A priority patent/EP3518978A1/fr
Priority to MX2019003520A priority patent/MX2019003520A/es
Priority to IL265535A priority patent/IL265535B/en
Priority to AU2017336199A priority patent/AU2017336199B2/en
Priority to US16/335,487 priority patent/US11241476B2/en
Priority to KR1020197008819A priority patent/KR102611788B1/ko
Application filed by Camurus Ab filed Critical Camurus Ab
Priority to JP2019516405A priority patent/JP7138626B2/ja
Priority to IL295457A priority patent/IL295457A/en
Priority to CA3038412A priority patent/CA3038412A1/fr
Priority to CN201780059020.8A priority patent/CN109789214B/zh
Publication of WO2018060212A1 publication Critical patent/WO2018060212A1/fr
Priority to US17/586,014 priority patent/US20220257694A1/en
Priority to US18/161,828 priority patent/US20230285502A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/02—Peptides of undefined number of amino acids; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/1796—Receptors; Cell surface antigens; Cell surface determinants for hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A61K9/1274—Non-vesicle bilayer structures, e.g. liquid crystals, tubules, cubic phases, cochleates; Sponge phases
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to mixtures comprising lipids and an antioxidant.
  • the present invention also relates to formulation precursors (pre-formulations) that upon exposure to water or aqueous media, such as body fluids, spontaneously undergo a phase transition thereby forming a controlled release matrix.
  • the invention relates to mixtures, pre-formulations and compositions having an improved resistance to oxidation.
  • bioactive agents including pharmaceuticals, nutrients, vitamins and so forth have a "functional window”. That is to say that there is a range of concentrations over which these agents can be observed to provide some biological effect. Where the concentration in the appropriate part of the body (e.g. locally or as demonstrated by serum concentration) falls below a certain level, no beneficial effect can be attributed to the agent. Similarly, there is generally an upper concentration level above which no further benefit is derived by increasing the concentration. In some cases increasing the concentration above a particular level results in undesirable or even dangerous effects.
  • bioactive agents have a long biological half-life and/or a wide functional window and thus may be administered occasionally, maintaining a functional biological concentration over a substantial period of time (e.g. 6 hours to several days).
  • rate of clearance is high and/or the functional window is narrow and thus to maintain a biological concentration within this window regular (or even continuous) doses of a small amount are required.
  • non-oral routes of administration e.g. parenteral administration
  • self-administration may be difficult and thus cause inconvenience and/or poor compliance.
  • Some patients undergoing treatment will typically require a therapeutic dose to be maintained for a considerable period and/or ongoing treatment for many months or years.
  • a depot system allowing loading and controlled release of a larger dose over a longer period would offer a considerable advantage over conventional delivery systems.
  • compositions of the present invention generate a non-lamellar liquid crystalline phase following administration.
  • non-lamellar phase structures such as liquid crystalline phases
  • a most effective lipid depot system is described in WO2005/117830, and a highly preferred lipid depot is described in that document.
  • Lipid controlled-release delivery systems have been developed with active agents including GLP-1 (WO2006/131730), somatostatin analogues (WO2006/075124), LHRH analogues (WO2006/075125), as well as non-peptides such as buprenorphine (WO2014/016428).
  • active agents including GLP-1 (WO2006/131730), somatostatin analogues (WO2006/075124), LHRH analogues (WO2006/075125), as well as non-peptides such as buprenorphine (WO2014/016428).
  • Lipid systems are also of value in treatment in their own right and need not include active agents.
  • the FDA approved oral liquid episil ® alleviates the pain caused by oral mucositis and other inflammatory conditions of the mouth by forming a lipid barrier in the oral cavity, but does not require any active agent.
  • GDO glycerol dioleate
  • PC phosphatidyl choline
  • sustained released formulations can be produced with a wide variety of other lipid components including tocopherol (WO2006/075123), derivatives of sorbitol (WO2016/102683), triglycerides
  • Both the lipid components, particularly unsaturated lipids, and any active agent contained in the pre- formulation or sustained release composition are susceptible to oxidation, either during storage or in vivo. It is desirable to decrease the extent of oxidation since oxidation processes may reduce the content of active agent and/or contribute to the formation of unwanted decomposition products. This in turn reduces the shelf life of a product.
  • One particular factor contributing to oxidation in lipid compositions is the presence of trace amounts of metal ions, particularly transition metals such as iron (Fe). Even when the lipid components are of high purity grade it is often difficult to entirely remove traces of such ions. It is thought that equipment used for the manufacture of lipid formulations commonly includes stainless steel which can leach small amounts of metal ions (particularly Fe) into the mixture. It is therefore common to include an antioxidant in lipid formulations. These generally function by chelating any metal ions, thereby hindering their participation in oxidation processes.
  • any antioxidant must be soluble in the lipid mixture, e.g. pre- formulation. It is described in WO2012/160213 that a carefully controlled amount of water can be included in lipid pre-formulations without causing a phase change into a liquid crystalline phase. In pre-formulations containing an appreciable aqueous content, it may be possible to include an effective amount of a water-soluble antioxidant such as ascorbic acid, inorganic salts of metal chelators, such as ethylenediaminetetraacetic acid (EDTA) (e.g. sodium or calcium salts) and citric acid. However, for certain active agents it may be necessary to avoid prolonged exposure to water during storage (e.g.
  • EDTA ethylenediaminetetraacetic acid
  • lipid formulations having a low water content it is not possible to use conventional water-soluble antioxidants since these may not have the requisite solubility in a substantially water-free lipid environment. It would therefore be advantageous to provide an antioxidant which is soluble in a substantially water- free lipid environment and which limits or prevents the oxidative degradation of the lipid components of the mixture, e.g. pre- formulation, and any active agent contained within. This is particularly the case for metal chelating agents such as EDTA where the standard inorganic salts (sodium or calcium) are non- soluble or have negligible solubility in non-aqueous environments (e.g. lipid matrices).
  • metal chelating agents such as EDTA where the standard inorganic salts (sodium or calcium) are non- soluble or have negligible solubility in non-aqueous environments (e.g. lipid matrices).
  • WO2010/020794 i.e. those based on GDO, SPC and an organic solvent such as ethanol.
  • alkylammonium EDTA salts are believed to have an effect on decreasing the decomposition by the expected mechanism of sequestering metal ions, the present invention may in some embodiments improve oxidation resistance above the level that can be accounted for solely by this mechanism.
  • alkylammonium EDTA salts can prevent, or substantially decrease the rate of, oxidation of a wide variety of lipid components and/or active agents contained therein.
  • the inventors have found that the inclusion of alkylammonium EDTA can substantially reduce the loss of assay of active agent in drug samples tested in stability studies and thus increases shelf-life of the drug product.
  • EDTA salts have the advantage that they are inexpensive, easily produced with a wide variety of countercations, and are generally regarded as safe (and are widely used e.g. in pharmaceutical applications).
  • the stabilizing and shelf-life extending effect of alkylammonium EDTA as found by the inventors may be not only related to the prevention or reduction of oxidation reactions but may be also related to the prevention or reduction of other chemical degradation reactions, e.g. hydrolysis, acylation, deamidation.
  • the invention provides a mixture of:
  • an alkyl ammonium EDTA salt e.g. comprising an anion of
  • the mixture has a water content in the range of 0 to 1.0 wt%.
  • ethylenediaminetetraacetic acid analogues and their corresponding anions will typically be as described herein below.
  • the present invention also provides a pharmaceutical formulation comprising an appropriate combination of lipid excipients, organic solvent, and an alkylammonium EDTA salt, that can be used as a depot-precursor formulation (referred to herein for brevity as a pre-formulation) to address one or more of the needs described above.
  • a pharmaceutical formulation comprising an appropriate combination of lipid excipients, organic solvent, and an alkylammonium EDTA salt, that can be used as a depot-precursor formulation (referred to herein for brevity as a pre-formulation) to address one or more of the needs described above.
  • the invention therefore provides a pre-formulation comprising: i) a lipid mixture comprising:
  • the pre-formulation has a water content in the range of 0 to 1.0 wt%.
  • the pre-formulation forms, or is capable of forming, at least one liquid crystalline phase structure upon contact with excess aqueous fluid.
  • the “lipid mixture” may be a "lipid controlled-release matrix”.
  • GDO glycerol dioleate
  • PC phosphatidyl choline
  • ethanol glycerol dioleate
  • the pre-formulation of all embodiments may further comprise an active agent, as described herein.
  • the pre-formulations are highly useful for the controlled and sustained release of an active agent, especially those requiring or benefiting from a very flat release profile and/or minimal "burst" upon administration.
  • the invention therefore provides for a mixture of:
  • a lipid mixture comprising: a) at least one of a mono-, di- or tri-acyl lipid and/or a tocopherol;
  • an alkyl ammonium EDTA salt e.g. comprising an anion of
  • the mixture has a water content in the range of 0 to 1.0 wt%
  • the pre-formulation forms, or is capable of forming, at least one liquid crystalline phase structure upon contact with excess aqueous fluid.
  • Bioactive agents may be any compound having a desired biological or physiological effect, such as a peptide, protein, drug, antigen, nutrient, cosmetic, fragrance, flavouring, diagnostic, pharmaceutical, vitamin, or dietary agent and will be formulated at a level sufficient to provide an in vivo concentration at a functional level (including local concentrations for topical compositions).
  • the "active agent” is a natural or synthetic peptide or non-peptide drug Active Pharmaceutical Ingredient (API) which provides a therapeutic, palliative and/or prophylactic effect when administered to a suitable subject (typically being one in need of such an effect).
  • the invention therefore provides a method for the treatment of a human or non-human mammalian subject comprising administering to said subject a pre-formulation as described herein.
  • a method may be for the treatment of a human or non-human mammalian subject in need thereof to combat, (e.g.
  • glucagonomas elevated growth hormone (GH), elevated insulin-like growth factor I (IGF-I), varicial bleeding (especially espohageal), chemotherapy induced gastro intestinal problems (such as diarrhea), lymphorrhea, diabetic retinopathy, thyroid eye disease, obesity, pancreatitis, and related conditions.
  • GH growth hormone
  • IGF-I insulin-like growth factor I
  • varicial bleeding especially espohageal
  • chemotherapy induced gastro intestinal problems such as diarrhea
  • lymphorrhea is at least one somatostatin analogue, as described herein.
  • the preformulations as described herein for use in such methods form a further aspect of the invention.
  • the present invention provides the use of a low viscosity mixture of:
  • a low viscosity pre- formulation medicament for use in the in vivo formation of a depot for treatment of at least one condition selected from acromegaly, cancers, carcinomas, melanomas, tumours expressing at least one somatostatin receptor, sst(2)-positive tumours, sst(5)-positive tumours, prostate cancers, gastro-entero-pancreatic endocrine tumours, gastro-entero-pancreatic neuroendocrine (GEP NE) tumours, lung NE tumours (lung NET), carcinoid tumours, insulinomas, gastrinomas, vasoactive intestinal peptide (VIP) tumours and glucagonomas, TSH-secreting pituitary adenomas, elevated growth hormone (GH), elevated insulin-like growth factor I (IGF-I), varicial bleeding (especially espohageal), chemotherapy induced gastro intestinal problems (such as diarrhea), lymphorrhea, diabetic retinopathy, thyroid eye disease, obesity
  • Certain active agents e.g. certain peptides
  • benefits which are cosmetic rather than (or in addition to) therapeutic in nature. Such effects include weight-loss and/or hunger suppression as well as control over skin or hair pigmentation, hair growth etc.
  • the present invention therefore additionally provides a method of cosmetic treatment of a human or non-human mammalian subject comprising administering to said subject a pre-formulation as described herein. Such a cosmetic method will generally not be a method of therapy (i.e. will not have therapeutic or medical benefit).
  • One of the advantages of the formulations of the present invention over many other controlled-release compositions is that they are stable to storage in their final form and thus little or no preparation is required at the time of administration.
  • the invention therefore provides a pre-filled administration device containing a pre-formulation as described herein.
  • a pre-filled administration device containing a pre-formulation as described herein.
  • Such a device will generally provide either a single administration or multiple administrations of a composition which will deliver, for example, a dosage of active agent in the range of 1 ⁇ g to 15 mg/day, such as 0.1 mg to 15 mg/day or 1 ⁇ g to 5 mg/day.
  • the invention provides a kit comprising said administration device according to the invention.
  • the kit can optionally contain instructions for subcutaneous or intramuscular administration of said pre-formulation. All pre-formulations described herein are suitable for use in such a kit and may thus be contained therein.
  • kits of the invention can optionally include additional administration components such as needles, swabs, and the like and will optionally contain instructions for administration.
  • the invention provides an alkylammonium EDTA salt comprising at least one alkyl ammonium cation of formula NR'R ⁇ R 41 ⁇ as defined herein, with the proviso that the alkylammonium cation is not trimethylammonium,
  • FIG. 1 Octreotide assay of Samples 55-60 as a function of EDTA concentration (0-750 ppm or 0-0.075 wt%) at three time points (0, 1 and 2 months) after storage at 40°C/75% RH.
  • Figure 3. OCT assay in SPC/GDO/EtOH/PG based formulations in the absence (Sample 61) and presence of 100 ppm EDTA (Sample 62) as a function of time at 25°C/60% RH. Formulations were stored in pre-filled glass syringes.
  • FIG. 7 OCT assay in SPC/GDO/EtOH/PG based formulations in the absence (Sample 79) and presence of 100 ppm EDTA solubilized in the lipid formulation by the use of ETA (Sample 84), DiETA (Sample 85) or ethylenediamine (Sample 86) as a function of time at 40°C/75% RH. Formulations were stored in vials with normal air in the headspace.
  • FIG. 8 OCT assay in SPC/GDO/EtOH/PG (Sample 79 - reference without EDTA, and Sample 84 with 100 ppm EDTA) based formulations as a function of time at 40°C/75% RH. Formulations were stored in vials with normal air in the headspace.
  • FIG. 15 Vial headspace oxygen concentration for SPC/GDO (50/50 w/w) based formulations without (Samples 103 and 104) and with 100 ppm EDTA (105 and 106) in the absence (a) and presence of 5 ppm Fe (b) as a function of time at 60°C/ambient RH. Formulations were stored in vials with normal air in the headspace.
  • FIG. 17 Vial headspace oxygen concentration for SPC/GDO (50/50 w/w) based formulations without (Samples 103 and 104) and with 100 ppm EDTA (105 and 106) in the absence (a) and presence of 5 ppm Fe 3+ (b) as a function of time at 40°C/75% RH. Formulations were stored in vials with normal air in the headspace.
  • Figure 18. Vial headspace oxygen concentration for SPC/GDO (35/65 w/w) based formulations without (Samples 107 and 108) and with 100 ppm EDTA (109 and 1 10) in the absence (a) and presence of 5 ppm Fe 3+ (b) as a function of time at 40°C/75% RH. Formulations were stored in vials with normal air in the headspace.
  • Lipids and oils are prone to oxidation. Mixtures which comprise lipids or oils may therefore gradually decrease in purity over time e.g. during storage or use. This is undesirable and may lead to unwanted changes in the physical and/or chemical properties of the mixture. It is particularly important to minimise the amount of breakdown products in mixtures having a pharmaceutical use, since breakdown products may be harmful to a patient and in any case often have to be kept within tightly controlled limits.
  • the mixtures of the present invention are substantially non-aqueous and include at least one lipid and/or oil (component i) and at least one alkylammonium EDTA salt (component ii).
  • the mixture is a pre-formulation.
  • the pre- formulations of the present invention are lipid-based, are substantially non-aqueous and form a depot composition upon contact with an aqueous fluid.
  • the terms "formulation " or "pre-formulation” relate to the mixture of components (i) and (ii) (component (i) comprising components (a), (c), and optionally (b) and (d)), which is typically of low viscosity.
  • the term "depot” relates to the composition which is formed upon exposure of the pre-formulation to excess aqueous fluid, e.g. as occurs during numerous parenteral administration routes. Without wishing to be bound by theory, it is thought that this change is brought about at least in part by exchange of solvent (c) for aqueous fluid.
  • the depot typically has a much higher viscosity than the corresponding pre-formulation and provides for the gradual release of any active agent contained within the depot.
  • the formulations of the present invention generate a non- lamellar phase (e.g. non-lamellar liquid crystalline phase) following administration.
  • non-lamellar phase structures such as liquid crystalline phases
  • lipid depot system A most effective lipid depot system is described in WO2005/117830, and a suitable lipid matrix for use in the present invention is described in that document, the full disclosure of which is hereby incorporated herein by reference.
  • the pre-formulation according to the invention has an L 2 phase (liquid phase) structure or is a liquid solution or molecular solution.
  • % are specified by weight herein throughout, unless otherwise indicated. Percent (%) by weight may be abbreviated e.g. as wt%. Furthermore, the % by weight indicated is the % of the total pre-formulation including all of the components indicated herein, unless otherwise indicated. Where a percentage by weight is given in relation to component (d) the weight relates to the amount of free base (e.g. where a salt is used), unless otherwise indicated. In certain Examples, the wt% of a specified salt is provided but is indicated where appropriate and may be readily converted to the corresponding weight of free base.
  • free base e.g. where a salt is used
  • the pre-formulations can optionally consist of essentially only the components indicated herein (including where appropriate additional optional components indicated herein below and in the attached claims) and in one aspect consist entirely of such components.
  • lipid-based pre-formulations described herein comprise lipid mixture (i) which includes lipid components (a) an organic solvent (c), and optionally (b) and (d), and an alkylammonium EDTA salt (ii).
  • the present inventors have now surprisingly established that by appropriate choice of antioxidant, the oxidation resistance of the lipid and/or oil, and in the case of pre- formulations, any active agent contained in the pre-formulation, can be significantly improved.
  • various alkylammonium EDTA salts are known, for instance from Scott and Kyffin (Biochem. J. (1978) 169, 697-701), their use as an antioxidant in lipid systems and compatibility with such formulations has been hitherto unknown. Scott and Kyffin describe the use of soluble EDTA salts in the demineralisation of bone samples, where EDTA acts as a sequestering agent.
  • a particularly suitable solution is said to be 80% aqueous ethanol containing 0.2 M trimethylammonium EDTA. No use in lipid formulations nor solubility in lipids is suggested.
  • the purpose of the EDTA salt in the present invention is as a preservative or stability enhancing agent in lipid formulations, and is very different from that described previously.
  • the mixture comprises at least one lipid and/or oil (component i) and has a water content of 0-1.0 wt%. Mixtures of lipids, mixtures of oils, or mixtures of both lipids and oils may be used as component i).
  • oil refers to saturated or unsaturated C5-C70
  • oils for use in the invention are saturated or unsaturated C10-C60 hydrocarbons, preferably saturated or unsaturated C10-C40 hydrocarbons.
  • component i) is an oil which is suitable for use a lubricant.
  • oils will typically be saturated C10-C40 hydrocarbons. It is desirable that lubricants are resistant to oxidation, because oxidation tends to increase the viscosity of the lubricant.
  • non-polar "tail” groups include C6-C32 alkyl and alkenyl groups, which are typically present as long chain carboxylic acids or the esters thereof. These are often described by reference to the number of carbon atoms and the number of unsaturations in the carbon chain. Thus, CX:Z indicates a hydrocarbon chain having X carbon atoms and Z unsaturations.
  • this number includes the carbon atom of the -C(0)0- moiety, as is conventional in the art.
  • typical non-polar chains are based on the fatty acids of natural ester lipids, including caproic, caprylic, capric, lauric, myristic, palmitic, phytanic, palmitolic, stearic, oleic, elaidic, linoleic, linolenic, arachidonic, behenic or lignoceric acids, or the corresponding alcohols.
  • Preferable non-polar chains are palmitic, stearic, oleic and linoleic acids, particularly oleic acid.
  • the lipid(s) may be saturated or unsaturated, but preferably comprise at least 1 wt% unsaturated lipid (based on the total lipid content), such as at least 5 wt% (5-100%), at least 15 wt% (15-100 %), at least 30 wt% (30-100%), at least 50 wt% (50-100%) or at least 80 wt% (80-100%).
  • component i) is a single fatty acid / fatty acid ester or mixture of fatty acids / fatty acid esters.
  • component i) will comprise a mixture of saturated and unsaturated fatty acids.
  • the lipid(s) and/or oil(s) are extracted from a natural source.
  • component i) is an edible lipid such as almond oil, avocado oil, butter, canola oil, castor oil, coconut oil, corn oil, cottonseed oil, flaxseed oil, ghee, lard, linseed oil, macadamia oil, margarine, mustard oil, olive oil, palm oil, peanut oil, pumpkin seed oil, rice bran oil, safflower oil, sesame oil, soybean oil, sunflower oil, tea seed oil, vegetable oil or walnut oil.
  • the above edible lipids are "lipids” rather than “oils” in the sense of component (i) because they contain fatty acids, particularly in the form of fatty acid esters, rather than hydrocarbons.
  • component i) is as defined for component a) or b) as described in subsequent sections.
  • the mixture consists essentially of, or consists of, components i) and ii).
  • a pre- formulation is a subcategory of the "mixtures” describe above in which component i) is a lipid mixture and comprises at least one neutral lipid "component a)" and optionally at least one phospholipid "component b)". Pre-formulations additionally comprise component c) and optionally component d) as described below.
  • Preferable ranges for component a) are 20-90 wt.% of the pre-formulation, preferably 30-70 wt.%, more preferably 33-60%) (e.g. 43-60%>), particularly 38 to 43%.
  • Component "a” as indicated herein is at least one mono-, di- or triacyl lipid comprising a polar "head” group and at least one non-polar "tail” group.
  • component a) may comprise or consist of tocopherol(s).
  • component a) comprises at least one neutral di-acyl lipid (having no net charge at physiological pH).
  • acyl lipid relates to a lipid component containing a polyol "head” group and one or more apolar "tail groups".
  • the polyol may be glycerol, a sugar or a hexitan such as sorbitan.
  • hexitan denotes a hexitol of formula HOCH 2 (CHOH) 4 CH 2 OH which has cyclised by formally losing one equivalent of water, to form a five or six membered ring, preferably a five membered furanose ring.
  • Sorbitan is a particularly suitable "head group", particularly as a component of a mono-acyl lipid component in certain embodiments.
  • the lipid component comprises a glycerol head group with two or three apolar tail groups.
  • the two or three non-polar groups may have the same or a differing number of carbon atoms and may each independently be saturated or unsaturated.
  • non-polar groups include C6-C32 alkyl and alkenyl groups, which are typically present as the esters of long chain carboxylic acids. These are often described by reference to the number of carbon atoms and the number of unsaturations in the carbon chain.
  • CX:Z indicates a hydrocarbon chain having X carbon atoms and Z unsaturations.
  • typical non-polar chains are based on the fatty acids of natural ester lipids, including caproic, caprylic, capric, lauric, myristic, palmitic, phytanic, palmitolic, stearic, oleic, elaidic, linoleic, linolenic, arachidonic, behenic or lignoceric acids, or the corresponding alcohols.
  • Preferable non-polar chains are palmitic, stearic, oleic and linoleic acids, particularly oleic acid.
  • CI 8 lipids e.g. a diacyl glycerol (DAG) having one or more CI 8:0, CI 8:1, CI 8:2 or CI 8:3 non-polar groups
  • DAG diacyl glycerol
  • GDO glycerol dioleate
  • GDL glycerol dilinoleate
  • GDO and other diacyl glycerols may be derived from natural sources, there is generally a certain proportion of "contaminant" lipid having other chain lengths etc.
  • pure GDO is a di-ester of glycerol and two CI 8: 1 fatty acids. Any other diacyl glycerol is considered to be an impurity.
  • GDO as used herein is thus used to indicate any commercial grade of GDO with concomitant impurities (i.e. GDO of commercial purity). These impurities may be separated and removed by purification but providing the grade is consistent this is rarely necessary.
  • GDO may be essentially chemically pure GDO, such as at least 70%> pure, preferably at least 75 %> pure and more preferably at least 80%) pure GDO.
  • the CI 8: 1 content of GDO referred to herein may be around 80%, preferably at least 85% and more preferably at least 90%.
  • any material used, including component a), may potentially include unavoidable trace impurities of metals, optionally including heavy metals.
  • a typical maximum concentration of heavy metals (or elemental impurities) in GDO is 5 ppm.
  • the common presence of these metal components and their sequestration in the various aspects of the present invention may be at least partially responsible for the additional stability observed.
  • a more common issue may be the presence of iron ions, which may be absorbed from iron-based alloy materials used in handling/storage of the materials.
  • Optional component "b" in the preferred lipid matrices of the present invention is at least one phospholipid. It is known from WO2016/066655 that lipid slow-release matrices based on triacyl lipids can form depot compositions on exposure to aqueous fluids without the need for a phospholipid component to be present, though a phospholipid may also be present.
  • component a) comprises, consists or consists essentially of a triacyl lipid(s) and component b) is optional. However , if component a) is greater than 50% mono-acyl or diacyl lipids, or a tocopherol, or mixtures of any of these components, then a phospholipid component b) will preferably be present.
  • component a) is less than 50% (e.g. 0 to 45%) triacyl lipid (based on the total amount of component a)) and component b) is present (e.g. at 20 to 80 wt% of the pre-formulation).
  • preferable ranges of component b) are 20-80 wt.% of the pre- formulation, preferably 30-70 wt.%>, more preferably 33-55%) (e.g. 35-55%), particularly 38 to 43%.
  • ratios of a:b are typically 40:60 to 70:30, preferably 45:55 to 55:45 and more preferably 40:60 to 54:46, such as 45:55 to 54:46 or 47:53 to 53:47.
  • Ratios of around 50:50 e.g. 49:51 to 51 :49 are highly effective in certain embodiments.
  • Preferred phospholipid polar "head” groups include phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine and phosphatidylinositol. Most preferred are phosphatidyl choline (PC) and phosphatidyl ethanolamine (PE), especially PC.
  • this component comprises a polar head group and at least one non-polar tail group.
  • the difference between components a) and b) lies principally in the polar group.
  • the non-polar portions may thus suitably be derived from the fatty acids or corresponding alcohols considered above for component a).
  • the phospholipid will contain two non-polar groups. Again, CI 8 groups are preferred and may be combined with any other suitable non-polar group, particularly C16 groups.
  • the phospholipid portion may be derived from a natural source.
  • suitable sources of phospholipids include egg, heart (e.g. bovine), brain, liver (e.g. bovine) and plant sources including soybean.
  • Such sources may provide one or more constituents of component b, which may comprise any mixture of
  • the PC component preferably contains at least 50% soy PC or egg PC, more preferably at least 75%) soy PC or egg PC and most preferably essentially pure soy PC or egg PC.
  • component b) comprises PC.
  • the PC is derived from soy.
  • the PC comprises 18:2 fatty acids as the primary fatty acid component with 16:0 and/or 18: 1 as the secondary fatty acid components. These are preferably present in the PC at a ratio of between 1.5: 1 and 6: 1.
  • PC having approximately 60-65% 18:2, 10 to 20% 16:0, 5-15% 18: 1, with the balance predominantly other 16 carbon and 18 carbon fatty acids is preferred and is typical of soy PC.
  • the PC component may comprise synthetic dioleoyl PC (DOPC).
  • DOPC synthetic dioleoyl PC
  • the PC component preferably contains at least 50% synthetic dioleoyl PC, more preferably at least 75% synthetic dioleoyl PC and most preferably essentially pure synthetic dioleoyl PC. Any remaining PC is preferably soy or egg PC as above.
  • the pre-formulations of the invention are to be administered to a subject, possibly with the inclusion of an active agent, it is important that the components are biocompatible.
  • the preferred lipid matrices for use in the pre- formulations of the present invention are highly advantageous since tocopherol, PC and acyl glycerols, particularly DAGs, are well tolerated and are broken down in vivo into components that are naturally present in the mammalian body.
  • component b) may include unavoidable trace impurities of heavy metals. According to the certificates of analysis for commercially available soy PC (e.g. from Lipoid), a typical maximum concentration of heavy metals (or elemental impurities) in soy PC is 10 ppm.
  • Synthetic or highly purified PCs such as dioleoyl phosphatidyl choline (DOPC) are highly appropriate as all or part of component b).
  • the synthetic dioleoyl PC is most preferably l,2-dioleoyl-sn-glycero-3-phosphocholine, and other synthetic PC components include DDPC (l,2-Didecanoyl-sn-glycero-3-phosphocholine);
  • a particularly favoured combination of components a) and b) are GDO with PC, especially GDO with soy PC and/or DOPC.
  • Appropriate amounts of each component suitable for the combination are those amounts indicated herein for the individual components in any combination. This applies also to any combinations of components indicated herein, where context allows.
  • Component c) of the pre-formulations of the invention is at least one biocompatible organic solvent. Since the pre- formulation is to generate a depot composition following administration (e.g. in vivo), typically upon contact with excess aqueous fluid, it is desirable that this solvent be tolerable to the subject and be capable of mixing with the aqueous fluid, and/or diffusing or dissolving out of the pre- formulation into the aqueous fluid. Solvents having at least moderate water solubility are thus preferred. As will be described hereinafter, component c) may include a polar co-solvent.
  • Component c) comprises or consists of at least one solvent selected from the group consisting of: alcohols, amines, amides or esters.
  • component c) comprises at least a mono-alcoholic solvent.
  • component c) comprises ethanol, propanol, iso-propanol, or mixtures thereof. It is particularly preferred the component c) comprises or consists of ethanol.
  • Component c) may comprise or consist of a mono-alcoholic solvent, preferably ethanol, and a polar co-solvent. Mixtures comprising or consisting of ethanol and propylene glycol are also highly preferred.
  • the amount of component c) in the pre-formulation will have a considerable effect upon several features.
  • the viscosity and the rate (and duration) of release may alter significantly with the solvent level.
  • the amount of solvent will thus be at least sufficient to provide a low viscosity mixture but will additionally be determined so as to provide the desired release rate.
  • a level of 1 to 30%, particularly 2 to 20%> solvent will provide suitable release and viscosity properties.
  • levels of 2 to 18%, such as 2 to 16%, especially 2 to 15% are preferred.
  • the amount of component c) in the pre-formulations of the invention will be at least sufficient to provide a low viscosity mixture (e.g. a molecular solution) of components a), c) and ii) (components b) and d) being optional as described herein), and will be easily determined for any particular combination of components by standard methods.
  • a low viscosity mixture e.g. a molecular solution
  • components a), c) and ii) (components b) and d) being optional as described herein
  • phase behaviour may be analysed by techniques such as visual observation in combination with polarized light microscopy, X-ray scattering and diffraction techniques, nuclear magnetic resonance, and cryo-transmission electron microscopy (cryo-TEM) to look for solutions, L 2 or L 3 phases, or liquid crystalline phases or as in the case of cryoTEM, dispersed fragments of such phases.
  • Viscosity may be measured directly by standard means. As described above, an appropriate practical viscosity is that which can effectively be syringed and particularly sterile filtered. This will be assessed easily as indicated herein.
  • a highly preferred combination for components a), b) and c) is GDO, soy PC and ethanol, especially GDO, soy PC and mixtures of ethanol and propylene glycol. As indicated above, appropriate amounts of each component suitable for the
  • component c) contains halogen substituted hydrocarbons since these tend to have lower biocompatibility.
  • Component c) as used herein may be a single solvent or a mixture of suitable solvents but will generally be of low viscosity.
  • the viscosity of the "low viscosity" solvent component c) should typically be no more than 18 mPas at 20°C. This is preferably no more than 15 mPas, more preferably no more than 10 mPas and most preferably no more than 7 mPas at 20° C.
  • component c) comprises a mono-alcoholic solvent and a polar co-solvent.
  • polar co-solvent defines a solvent having a dielectric constant (diel) of at least 28 at 25°C, more preferably at least 30 at 25°C but is not water or any aqueous fluid.
  • Highly suitable examples include propylene glycol (diel -32), and N- methyl-2-pyrrolidone (NMP, diel -32).
  • the preferred levels of component c) recited herein apply equally to mixtures of mono-alcoholic solvent and a polar co-solvent unless context permits otherwise.
  • component c) comprises, consists essentially of, or consists of a mixture of a mono-alcoholic solvent and a polar co-solvent.
  • the polar co-solvent may in one embodiment be a di-alcoholic C3-C6 organic solvent, i.e. a C3-C6 organic solvent comprising two hydroxy groups.
  • the di-alcoholic solvent is preferably propylene glycol.
  • a polar co-solvent is included at a level of 2 to 12 wt.% of the pre-formulation, such as 3 to 10 wt.%, especially 4 to 9 wt.%. This level is counted as part of the ranges recited above for component c).
  • component c) comprises, consists essentially of, or consists of a mixture of ethanol and propylene glycol (PG).
  • the ratio of mono-alcoholic solvent to polar co-solvent solvent is preferably in the range 20:80 to 70:30, preferably 30:70 to 70:30 (w/w), more preferably 40:60 to 60:40. Approximately equal amounts of mono- and di-alcoholic components are highly appropriate.
  • component c) is present at a level of 1 to 30% and comprises, consists or consists essentially of a mixture of ethanol and PG, wherein the ratio of ethanol to PG (w/w) is in the range of 30:70 to 70:30, preferably 40:60 to 60:40. More preferably component c) is present at a range of 5 to 15 wt% or 8 to 18 wt%, most preferably 8 - 18 % wt% and is a mixture of ethanol and PG in a ratio of 40:60 to 60:40 (w/w).
  • the total water level will remain as described in the various embodiments herein (e.g. 0.1 to 1.0 wt%).
  • Component ii) is an alkylammonium salt comprising an anion of EDTA
  • each R J -R 4 is independently H, or a linear or branched Cl-10 group (as described herein), with the proviso that at least one ofR ! -R 4 is not H.
  • n 1
  • ammonium salts containing more than one nitrogen atom such as ethylenediamine (NH 2 CH 2 CH 2 NH 2 ) it may be possible for a mixture of +1 and +2 cations to exist (i.e. N ⁇ C kC ⁇ N ⁇ and NH 3 CH 2 CH 2 NH 3 2+ ).
  • N ⁇ C kC ⁇ N ⁇ and NH 3 CH 2 CH 2 NH 3 2+ i.e. N ⁇ C kC ⁇ N ⁇ and NH 3 CH 2 CH 2 NH 3 2+ .
  • polycationic species may be prevented by providing an excess of the precursor amine as described below.
  • the person skilled in the art will appreciate when the formation of mixed cations is a possibility.
  • R 1 to R 4 may be the same or different, with the proviso that at least one of R 1 to R 4 is not H.
  • Preferably all of the substituent groups R 1 to R 4 which are not H are the same.
  • Preferred cations are therefore NRH 3 , NR 2 H 2 and NR 3 H or NR 4 wherein the "R" groups are the same.
  • Primary, secondary and tertiary ammonium cations are preferred to quaternary cations as the former can be easily prepared by combining the appropriate amine with EDTA as described below.
  • Each of R 1 to R 4 is independently H or a linear or branched Cl-10 alkyl, alkenyl or alkynyl group, preferably C1-C5. Most preferably each of R 1 to R 4 is a linear or branched CI -5 alkyl group, especially a linear C1-C5 or C1-C3 alkyl group.
  • Each R 1 to R 4 may independently be further substituted with one or more OH or NH 2 (or NH 3 ) groups.
  • the substituent may contain a maximum of m-l OH and/or NH2 groups per substituent. For instance, if Rl is C8 then Rl may contain up to 7 OH groups, especially one OH unit attached to each carbon atom other than the carbon atom directly joined to the ammonium N atom.
  • This embodiment is of particular relevance to the case in which the alkylammonium cation is derived from an aminopolyol (e.g. meglumine (MeNHCH 2 (CHOH) 4 CH 2 OH)).
  • Rl may contain up to 2 OH groups, such as serinol (NH 2 CH(CH 2 OH) 2 ).
  • at least one of R ⁇ is a linear Cl ⁇ group substituted with at least one OH or NH 2 group.
  • any two of the groups Rl to R4 taken together form a C4-C8, preferably C4-C6 ring, which may optionally contain one or more exocyclic OH or NH2 groups. If any two of the groups R 1 to R 4 together form a ring then a single endocyclic O or NH unit may also be present.
  • morpholine salts may be used (i.e. if any two of R 1 to R 4 together form a six- membered C4 ring containing one endocyclic O atom).
  • two of the groups R 1 to R 4 along with N together together form a morpholine ring, while the remaining groups R 1 to R 4 have the definition above.
  • Particularly preferred alkylammonium cations include those derived from N- protonation, or in a less preferred embodiment N-alkylation, of an amine selected from:
  • Ethanolamine "ETA” (NH 2 (CH 2 CH 2 OH)
  • Diethanolamine "DiETA” (NH(CH 2 CH 2 OH) 2 );
  • the mass of the alkylammonium cation of Formula (I) is below 500 amu, preferably below 350, especially below 250 amu.
  • Salts of EDTA containing the ethanolammonium ion (HOCH 2 CH 2 NH 3 ) are particularly preferred in the invention. It is most preferred that the EDTA salt is a salt of EDTA with ethanolamine (ETA), preferably EDTA with ETA only.
  • the invention relates to EDTA salts comprising an anion of EDTA and at least one alkylammonium cation of Formula (I) as previously described, with the proviso that the alkylammonium cation is not
  • the alkylammonium cation is thought to aid in increasing the lipid solubility the EDTA salt relative to a conventional metal (inorganic) EDTA salt such as disodium EDTA.
  • EDTA contains four carboxylic acid units the alkylammonium salt may comprise up to four ammonium cations and a tetraanionic EDTA anion.
  • EDTA may represent ethylenediammetetraacetic acid as such.
  • EDTA as indicated herein may include both
  • EDTA ethylenediammetetraacetic acid itself and EDTA analogues.
  • EDTA herein thus includes “EDTA and analogues thereof whenever context allows.
  • Suitable EDTA analogues are those containing at least one glycinate unit (i.e. the unit -NCH 2 COO-) within the molecule, preferably at least 2, at least 3 or at least 4 glycinate units.
  • Suitable EDTA analogues include:
  • Iminodiacetic acid - (NH(CH 2 C0 2 H) 2 ;
  • Nitrilotriacetic acid N(CH 2 C0 2 H) 3 ;
  • Pentetic acid* - N(CH 2 C0 2 H) 2 CH 2 CH 2 N(CH 2 C0 2 H)CH 2 CH 2 N(CH 2 C0 2 H) 2 ;
  • Egtazic acid N(CH 2 C0 2 H) 2 CH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 N(CH 2 C0 2 H) 2
  • the EDTA analogue has the structure indicated in Formula (II) below:
  • X is CH 2 , O or NR 4
  • R l s R 2 , R 3 and R 4 are each individually H or CH 2 C0 2 H, preferably CH 2 C0 2 H; or
  • Ri and R 3 together represent a covalent bond (i.e. the EDTA analogue is cyclic) and R 2 and R 4 are each individually H or CH 2 C0 2 H, preferably CH 2 C0 2 H.
  • Amounts of EDTA and ratios of EDTA to (d) defined herein apply equally to EDTA and EDTA analogues. In all embodiments it is preferred that EDTA is used as the counterion in component (ii).
  • the EDTA salt may be pre-formed and dissolved or dispersed in one or more of the components prior to forming the mixture, e.g. pre-formulation, or may be formed in situ. In situ formation is generally preferred for simplicity of operation.
  • a suitable method for preparing the alkylammonium EDTA salt involves dissolving EDTA (acid form) and the requisite alkylamine (base) in the solvent component (c), or in a solvent which is a precursor to (or sub-component of) the solvent component (c), and providing mixing until the solids are fully dissolved.
  • the EDTA salt may be pre-formed and dissolved or dispersed in component i).
  • a mono-amine at least 3.0, preferably at least 3.5 (e.g. 3.5 to 10) molar equivalents of amine (which is a precursor to the ammonium salt) are required relative to the amount of EDTA in order to solubilize the salt in the solvent component (c).
  • amine which is a precursor to the ammonium salt
  • the minimum ratio between the amine and EDTA necessary to solubilize the salt varies depending on the specific choice of alkylammonium salt.
  • an appropriate molar ratio can be achieved by experimentation by simply observing at what molar excess of alkylamine the solid EDTA fully dissolves in the solvent.
  • a greater than stoichiometric ratio of amine is added than is formally needed to form the tetraamonium EDTA salt.
  • efficient solubilisation of EDTA using TRIS may require 5.0 or more equivalents of amine.
  • the molar ratio to achieve adequate EDTA salt solubility may not be as high as for a mono-amine.
  • polyamines diamines, triamines etc
  • the required molar ratio may be lower than that for a mono-amine.
  • Suitable levels for polyamines may be 2.0 or more (e.g. 2.0 to 4.0), or 2.5 or more. Again, suitable levels can be found by optimisation.
  • the molar equivalents of amine discussed above may represent the molar ratio of mono-amine to EDTA or the ratio of amine moieties to EDTA where the amine (or mixture of amines) has more than one amine moiety in the molecule (either individually or on average for a mixture).
  • EDTA(Na) disodium EDTA
  • suitable/preferred solvents e.g. EtOH/PG
  • alkylamine e.g. ETA
  • a typical procedure for producing the salt therefore involves dissolving the free tetraacid EDTA (which may be a hydrate) in the solvent (c), or in a solvent which is a precursor to the solvent component (c), which comprises at least a mono-alcoholic solvent such as ethanol, and may also comprise a polar co-solvent as previously described, preferably in a mixture of ethanol and PG.
  • the requisite number of equivalents of alkylamine are then added and the mixture is agitated, e.g. by end- over-end rotation or magnetic stirring until the EDTA is dissolved, as can be established by visual observation. 24 h of mixing is usually adequate to ensure efficient solubility, e.g. in the case of the formation of an ETA/EDTA salt.
  • the salt in a solvent which is a precursor to the solvent component (c).
  • precursor it is meant that the solvent in which the EDTA salt is formed is not identical to the final composition of solvent component (c), but that the content of solvent(s) in the precursor can be adjusted to arrive at the final composition of the solvent (c) in the pre-formulation.
  • the salt may be formed in a mixture of EtOH:PG (1 :2) and additional ethanol added during or after salt formation in order to reach a final composition of EtOH:PG (1 : 1) for component (c).
  • the inventors have surprisingly established that above a certain ratio of alkylamine : EDTA the chemical stability of the active agent in the pre-formulation begins to decrease. This may be a result of reaction between the excess alkylamine and the active agent, either directly or via degradation products. Accordingly, it is preferred that the amount of alkylamine chosen is sufficient to fully solubilize all of the EDTA in the solvent component (c) but is not significantly beyond this level. It is preferred that the amount of alkylamine included is no more than 2 times the required level to achieve complete solubility, preferably no more than 1.5 times, preferably no more than 1.2 times. The amount of alkylamine necessary to fully solubilize ETDA in the solvent component (c) can be established by the methods described previously.
  • component (ii) comprises an alkylammonium counterion having only one amino or alkylamino group and the ratio of EDTA: the total of said alkylammonium counterion and any amine free base thereof in the pre-formulation is 1 : >3.0; preferably 1 : >3.5, most preferably in the range of 1 :3.0 to 1 : 10.
  • component (ii) comprises an alkylammonium counterion having two or more amino and/or alkylamino groups, wherein the ratio of EDTA: the total of said alkylammonium counterion and any amine free base thereof in the pre- formulation is 1 : >2.0; preferably in the range of 1 :2.0 to 1 :4.0.
  • the EDTA salt is an ETA salt of EDTA.
  • the solvent component (c) e.g. a mixture of EtOH/PG 50:50
  • the amount of ETA to EDTA is preferably no more than 7: 1.
  • the equivalents of ETA to EDTA are preferably in the range of 3.5 to 7 (mol/mol), preferably 3.5 to 5, most preferably 3.5 to 4.5. Most preferably 4 equivalents of ETA are used relative to the amount of EDTA (mol/mol).
  • the level of alkylammonium EDTA salt is chosen to ensure appropriate stability of the components of the lipid vehicle and active agent (if any) for the storage duration required and under the chosen storage conditions.
  • Factors to be considered when determining appropriate amounts of alkylammonium EDTA salt include: the reactivity of the lipid components and active agent (if any), the loading of active agent (if any), the molecular mass of the active agent, storage conditions (oxygen content, humidity, temperature), the duration of oxidative protection required and the concentration of metal ions present in the pre-formulation (which may catalyse decomposition processes).
  • the pre-formulation will typically include the EDTA salt at a level such that the ratio of EDTA salt to metal (e.g Fe, especially in the form of Fe(II) and Fe(III) ions) is at least around 2: 1 (mol/mol), i.e. the EDTA salt is present in at least a 2 times molar excess.
  • the molar ratio will be based upon the maximum estimated metal ion (especially Fe ion) concentration and EDTA provided in a ratio of around 2: 1 to this maximum estimate. The result in practice will then be 2:3 or greater molar ratio of EDTA to metal (e.g. Fe ions).
  • EDTA e.g. Fe ions
  • a suitable amount of EDTA salt in the pre-formulation will be 0.001-0.02 wt% (10-200 ppm), preferably 0.001-0.015 wt% (10-150 ppm), especially 0.002-0.015 wt% (20-150 ppm).
  • a particularly preferred level is 0.005- 0.015 wt.% (50-150 ppm), most preferably 0.008-0.012 wt.% (80-120 ppm).
  • a level of 100 ppm is suitable for protecting against up to 10 ppm of metal (iron
  • the levels of EDTA may range from 0.001 to 0.8 wt% (10 to 8000 ppm), 0.002 to 0.5 wt% (20 to 5000 ppm), 0.005 to 0.2 wt% (50 to 2000 ppm) or 0.01 to 0.1 wt% (100 to 1000 ppm) of the pre-formulation.
  • 0.001 to 0.8 wt% (10 to 8000 ppm) may range from 0.001 to 0.8 wt% (10 to 8000 ppm), 0.002 to 0.5 wt% (20 to 5000 ppm), 0.005 to 0.2 wt% (50 to 2000 ppm) or 0.01 to 0.1 wt% (100 to 1000 ppm) of the pre-formulation.
  • the level of EDTA may range from 0.001 to 0.050 wt% (10 to 500 ppm) of the mixture, e.g. pre-formulation, preferably 0.002 to 0.030 wt% (20 to 300 ppm) of the mixture.
  • the level of alkylamine to be added can be established once the optimum ratio of alkylamine to EDTA is found, as described in preceding sections.
  • the ratio of (ii) to (d) is in the range 1 : 1 to 1 :5000 (w/w), preferably 1 : 1 to 1 :500 (w/w), preferably in the range of 1 :50 to 1 :300.
  • EDTA salts containing an alkylammonium ion of Formula (I) allows for an antioxidant to be included in the mixture, e.g. pre-formulation, at low levels of water. It is however extremely difficult to completely eliminate all traces of water (especially from the raw materials). Even if essentially water- free
  • pre-formulations will typically be stored in ready- to-use form, e.g. in syringes and possibly under refrigerated conditions. Syringes are often not completely air-tight meaning that the level of water in the pre-formulation may increase to an appreciable level over time, e.g. over months, even if the initial level of water is insignificant.
  • the initial absolute level of water in the mixture is between 0 to 1.0 wt.%.
  • the water content is less than 1.0 wt.%, preferably less than 0.8 wt%, preferably less than 0.5 wt%.
  • the level of water is in the range of 0.1 to 0.9 wt.%, especially 0.2 to 0.8 wt.%. These levels refer to the absolute level of water and not added levels of water. Any unavoidable trace of water present within components a), b) or c) is included in this stated level of water. After 3 months of storage, the absolute water level is preferably no more than 1.5 wt%.
  • Absolute levels of water can be measured by methods well known in the art such as Karl Fischer titration.
  • the water content is preferably measured according to the procedure in United States Pharmacopoeia (USP 40 - NF 35, USP ⁇ 921> Water determination, Method la.
  • the pre-formulations of the present invention may contain one or more peptide or non-peptide active agents. It is emphasised that the surprising discovery that the oxidation of lipid pre-formulations having low levels of water (no more than 1.0%), and optionally any active agent contained therein can be reduced by the inclusion of particular EDTA salts herein described, is of very general applicability and therefore the nature of the bioactive agent is not particularly critical to the working of the invention. Indeed, since oxidation of the lipid components is reduced by the method of the invention, advantages of the present invention may be obtained independently of the nature or even presence of any active agent.
  • Bioactive agents may be any compound having a desired biological or physiological effect, such as a peptide, protein, drug, antigen, nutrient, cosmetic, fragrance, flavouring, diagnostic, pharmaceutical, vitamin, or dietary agent and will be formulated at a level sufficient to provide an in vivo concentration at a functional level (including local concentrations for topical compositions).
  • Most preferred active agents are pharmaceutical agents including drugs, vaccines, and diagnostic agents.
  • An especially preferred class of active agents is somatostatins and somatostatin analogues.
  • drugs which may be delivered by the composition of the present invention include, but are not limited to, antibacterial agents, immune modulating agents, including immunostimulants and immunosuppressants, anticancer and/or antiviral drugs such as nucleoside analogues, paclitaxel and derivatives thereof, anti inflammatory drugs/agents, such as non-steroidal anti inflammatory drugs and corticosteroids, cardiovascular drugs including cholesterol lowering and blood- pressure lowing agents, analgesics, anti-emetics including histamine HI, NK1 and 5-HT 3 receptor antagonists, corticosteroids and cannabinoids, antipsychotics and antidepressants including serotonin uptake inhibitors, prostaglandins and
  • Diagnostic agents include radionuclide labelled compounds and contrast agents including X-ray, ultrasound and MRI contrast enhancing agents.
  • Nutrients include vitamins, coenzymes, dietary supplements etc.
  • Particularly suitable active agents include those which would normally have a short residence time in the body due to rapid breakdown or excretion and those with poor oral bioavailability. These include peptide, protein and nucleic acid based active agents, hormones and other naturally occurring agents in their native or modified forms.
  • the agents are provided at a sustained level for a length of time which may stretch to days, weeks or even several months in spite of having rapid clearance rates. This offers obvious advantages in terms of stability and patient compliance over dosing multiple times each day for the same period.
  • the active agent thus has a biological half life (upon entry into the blood stream) of less than 1 day, preferably less than 12 hours and more preferably less than 6 hours. In some cases this may be as low as 1-3 hours or less.
  • Suitable agents are also those with poor oral bioavailability relative to that achieved by injection, for where the active agent also or alternatively has a bioavailability of below 20%, or preferably below 2%, especially below 0.2%, and most preferably below 0.1% in oral formulations.
  • bioactive agent to be formulated with the pre-formulations of the present invention will depend upon the functional dose and the period during which the depot composition formed upon administration is to provide sustained release. Typically, the dose formulated for a particular agent will be around the equivalent of the normal daily dose multiplied by the number of days the pre-formulation is to provide release. Evidently this amount will need to be tailored to take into account any adverse effects of a large dose at the beginning of treatment and so this will generally be the maximum dose used. The precise amount suitable in any case will readily be determined by suitable experimentation.
  • the pre-formulation of the invention may comprise one or more peptide active agents.
  • Peptide active agents may comprise 5 to 60 natural and/or synthetic amino acids, especially 5 to 50 or 5 to 40 amino acids.
  • Peptide and protein based active agents include human and veterinary drugs selected from the group consisting of adrenocorticotropic hormone (ACTH) and its fragments, angiotensin and its related peptides, antibodies and their fragments, antigens and their fragments, atrial natriuretic peptides, bioadhesive peptides, bradykinins and their related peptides, calcitonin peptides including calcitonin and amylin and their related peptides, vasoactive intestinal peptides (VIP) including growth hormone releasing hormone (GHRH), glucagon, and secretin, opioid peptides including proopiomelanocortin (POMC) peptides, enkephalin
  • ACTH adrenocorticotropic hormone
  • POMC proopiomelanocortin
  • pentapeptides pentapeptides, prodynorphin peptides and related peptides, pancreatic polypeptide- related peptides like neuropeptide (NPY), peptide YY (PYY), pancreatic
  • polypeptide PHY
  • cell surface receptor protein fragments chemotactic peptides, cyclosporins, cytokines, dynorphins and their related peptides, endorphins and P- lidotropin fragments, enkephalin and their related proteins, enzyme inhibitors, immunostimulating peptides and polyaminoacids, fibronectin fragments and their related peptides, gastrointestinal peptides, gonadotrophin-releasing hormone (GnRH) agonists and antagonist, glucagon-like peptides 1 and 2, growth hormone releasing peptides, immunostimulating peptides, insulins and insulin-like growth factors, interleukins, luthenizing hormone releasing hormones (LHRH) and their related peptides (which are equivalent to GnRH agonists as described below), melanocortin receptor agonists and antagonists, melanocyte stimulating hormones and their related peptides, nuclear localization signal related peptide
  • POMC adrenocorticotropic hormone
  • ACTH adrenocorticotropic hormone
  • the posterior pituitary hormones including vasopressin and oxytocin
  • the growth hormone family including growth hormone (GH), human chorionic somatomammotropin (hCS), prolactin (PRL), the pancreatic polypeptide family including PP, PYY and NPY
  • MCH melanin- concentrating hormone
  • MHC melanin- concentrating hormone
  • orexins gastrointestinal hormones and peptides including GLP-1 and GIP; ghrelin and obestatin; adipose tissue hormones and cytokines including leptin, adiponectin, and resistin; natriuretic hormones;
  • parathyroid hormone PTH
  • the calcitonin family with calcitonin and amylin the pancreatic hormones including insulin, glucagon and somatostatin.
  • All synthetic peptides designed to have similar receptor affinity spectrums as the above mentioned peptides are also very suitable for the invention.
  • a further considerable advantage of the depot compositions of the present invention is that active agents are released gradually over long periods without the need for repeated dosing.
  • the compositions are thus highly suitable for situations where patient compliance is difficult, unreliable or where a level dosage is highly important, such as mood-altering actives, those actives with a narrow therapeutic window, and those administered to children or to people whose lifestyle is incompatible with a reliable dosing regime and for "lifestyle" actives where the inconvenience of repeated dosing might outweigh the benefit of the active.
  • hormones used in children such as growth hormone, anti-addictive agents, and drugs used in treatment of poorly compliant populations, such as patients suffering from schizophrenia, Alzheimer, or Parkinson's disease, anti-depressants and anticonvulsants.
  • Cationic peptides and proteins are particularly suitable for use where a portion of the pre-formulation comprises an anionic amphiphile such as a fatty acid or anionic lipid, including phosphatidic acid, phosphatidylglycerol, phosphatidylserine.
  • preferred peptides or proteins include octreotide, lanreotide, calcitonin, oxytocin, interferon-beta and -gamma, interleukins 4, 5, 7 and 8 and other peptides or proteins having an isoelectric point above pH 7, especially above pH 8.
  • the composition of the invention is such that a reversed micellar cubic (I 2 ) phase, or a mixed phase including I 2 phase is formed upon exposure to aqueous fluids and a polar active agent is included in the composition.
  • polar active agents include peptide and protein actives, oligo nucleotides, and small water soluble actives, including those listed above.
  • peptide octreotide and other somatostatin related peptides include interferons alpha and beta, glucagon-like peptide 1 and glucagon-like peptide 2 receptor agonists, leuprorelin and other GnRH agonists, abarelix and other GnRH antagonists, granisetron and ondansetron and other 5-HT 3 receptor antagonists.
  • GnRH analogues form one particular class of active agents which may be included in formulations of the present invention.
  • Gonadotropin-releasing hormone agonists are synthetic peptides modelled after the hypothalamic neurohormone GnRH that interacts with the gonadotropin-releasing hormone receptor to elicit its biologic response, the release of the pituitary hormones follicle stimulating hormone (FSH) and luteinizing hormone (LH). GnRH agonists are useful in treatment of cancers that are
  • hormonally sensitive and where a hypogonadal state decreases the chances of a recurrence are commonly employed in the medical management of prostate cancer and have been used in patients with breast cancer.
  • Other indication areas include treatment of delaying puberty in individuals with precocious puberty, management of female disorders that are dependent on estrogen productions.
  • women with menorrhagia, endometriosis, adenomyosis, or uterine fibroids may receive GnRH agonists to suppress ovarian activity and induce a
  • GnRH-RAs Gonadotropin-re leasing hormone receptor agonists
  • leuprolide or leuprorelin
  • goserelin histrelin
  • triptorelin buserelin
  • deslorelin nafarelin and related peptides
  • GnRH-RAs form a preferred group of active agents for use in the present invention.
  • GnRH itself is a post-translationally modified decapeptide of structure pyro-Glu- His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH 2 (GnRH-I).
  • GNRH-II Two natural varients are also known, GNRH-II having 5-His, 7-Trp, 8-Tyr substitutions and GnRH III having 7-Trp, 8-Leu.
  • Several peptide analogues with agonistic properties are known, most of which have thelO-Gly-NH 2 replaced with N-Et-NH 2 .
  • Fertirelin has 10-Gly to N-Et-NH 2 substitution only, while analogues having additional substitutions over GnRH-I include Leuprorelin (Leuprolide), (6-D-Leu), Buserelin (6-Ser(Bu 1 )), Histrelin (6-d-His(Imbzl)), Deslorelin (6-d-Trp).
  • Another common nona-peptide agonist is Goserelin which is substituted with 6-Ser(Bu ) and has 10-Gly-NH 2 replaced by AzaGly-NH 2 .
  • Narafelin (6-d-Nal) and Triptorelin (6-d-Trp) both retain the 10-Gly-NH 2 group.
  • the structures of the two most common GnRH agonists (Leuprolide and Goserelin) are shown below as acetate salts.
  • Leuprolide pyro-Glu-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro- N-Et-NH 2 (acetate)
  • Goserelin pyro-Glu-His-Trp-Ser-Tyr-D-Ser(Bu )-Leu-Arg-Pro-Azgly-NH 2 (acetate)
  • GnRH antagonists are also known, again based on the GnRH-I structure. These include Abarelix (D-Ala-D-Phe-D-Ala-Ser-Tyr-D-Asp-Leu- LysCPr)-Pro-D-Ala), Antarelix (D-Nal-D-Phe-D-Pal-Ser-Phe-D-Hcit-Leu-LysCPr)- Pro-D-Ala); Cetrorelix (D-Nal-D-Phe-D-Pal-Ser-Tyr-D-Cit-Leu-Arg-Pro-D-Ala), Ganirelix (D-Nal-D-Phe-D-Pal-Ser-Tyr-D-hArg-Leu-HArg-Pro-D-Ala), Itrelix (D- Nal-D-Phe-D-Pal-Ser-NicLys-D- NicLys -Leu-Lys -Le
  • GnRH agonist such as leuprolide
  • LH and FSH gonadotropins
  • Leuprolide 's mechanism of action may also involve inhibition and/or induction of enzymes that control steroidogenesis.
  • Other mechanisms of action may include secretion of an LH molecule with altered biologic activity or impairment of normal pulsatile patterns of LH and FSH secretion.
  • a number of serious medical indications are related to and/or affected by the concentration of gonadal steroid hormones. These include certain neoplastic diseases, including cancers, especially of the breast and prostate, and benign prostatic hypertrophy; premature or delayed puberty in adolescents; hirsuitism; alzheimer's disease; and certain conditions relating to the reproductive system, such as hypogonadism, anovulation, amenorrhea, oligospermia, endometriosis, leiomyomata (uterine fibroids), premenstrual syndrome, and polycystic ovarian disease. Control of this system is also important in in vitro fertilisation methods.
  • pre-formulations of the present invention contain one or more GnRH analogues. Since GnRH is a peptide hormone, typical GnRH analogues will be peptides, especially of 12 or fewer amino acids.
  • peptides will be structurally related to GnRH I, II and/or III, and/or one or more of the known analogues, including those listed here.
  • Peptides may contain only amino acids selected from those 20 a-amino acids indicated in the genetic code, or more preferably may contain their isomers and other natural and non-natural amino acids, (generally ⁇ , ⁇ or ⁇ amino acids) and their analogues and derivatives.
  • Preferred amino acids include those listed above as constituents of the known GnRH analogues.
  • Amino acid derivatives are especially useful at the termini of the peptides, where the terminal amino or carboxy late group may be substituted by or with any other functional group such as hydroxy, alkoxy, carboxy, ester, amide, thio, amido, amino, alkyl amino, di- or tri-alkyl amino, alkyl (by which is meant, herein throughout Ci- Ci 2 alkyl, preferably Ci-C 6 alkyl e.g.
  • aryl e.g phenyl, benzyl, napthyl etc
  • other functional groups preferably with at least one heteroatom and preferably having no more than 10 atoms in total, more preferably no more than 6.
  • GnRH analogues are constrained peptides of 6 to 12 alpha- amino acids, of which particular examples include those indicated above, and particularly leuprolide and goserelin, of the sequences indicated above.
  • GnRH analogues any GnRH agonist or antagonist, preferably peptides, peptide derivatives or peptide analogues. Peptide derived GnRH agonists are most preferred, such as those indicated above and especially leuprolide or goserelin.
  • the GnRH analogue will generally be formulated as 0.02 to 12% by weight of the total pre- formulation (based on the amount of free base). Typical values will be 0.1 to 10%, preferably 0.2 to 8%> and more preferably 0.5 to 6%>. A GnRH analogue content of around 1-5% is most preferable. Doses of the GnRH analogue suitable for inclusion in the pre- formulation, and thus the volume of formulation used will depend upon the release rate (as controlled, for example by the solvent type and amount use) and release duration, as well as the desired therapeutic level, the activity of the specific agent, and the rate of clearance of the particular active chosen. Typically an amount of 0.1 to 500 mg per dose would be suitable for providing a therapeutic level for between 7 and 180 days.
  • the level will typically be around 1 to 120 mg (e.g. for a 30 to 180 day duration).
  • the amount of leuprolide will be around 0.02 to 1 mg per day between injections, for depots designed for release over 30 days to 1 year, preferably 3 to 6 months.
  • the stability of the active and linearity of the release rate will mean that the loading to duration may not be a linear relationship.
  • a depot administered every 30 days might have, for example 2 to 30 mg or a 90 day depot have 6 to 90 mg of active, such as one of the GnRH analogues indicated herein.
  • Somatostatin analogues form one particular class of active agents which may be included in formulations of the present invention.
  • Somatostatins (Growth Hormone Release Inhibiting Factors, SSTs) are natural peptide hormones with a wide distribution in animals, acting as neurotransmitters in the central nervous system, and having diverse paracrine/autocrine regulatory effects on several tissues.
  • SST-14 and SST-28 Two biologically active products are known in higher species, SST-14 and SST-28, the latter being a congener of SST-14 extended at the N-terminus.
  • SST-14 is a 14 residue cyclic peptide hormone having the sequence Ala-Gly-Cys- Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys, where the two cysteine residues are connected by a disulphide bridge to generate a type II ⁇ -turn at the key binding sequence of Phe-Trp-Lys-Thr.
  • the biological half-life of natural SST-14 is very short (1-3 minutes) and so it is not, in itself, a viable therapeutic in current formulations, but an increasing number of somatostatin receptor agonists are becoming available with higher activities and/or longer clearance times in vivo.
  • Somatostatin receptor agonists such as SST-14, SST-28, octreotide, lanreotide, vapreotide, pasireotide (SOM 230) and related peptides, are used or indicated in the treatment of a variety of conditions where they are typically administered over an extended period.
  • SRAs form a preferred group of active agents for use in the present invention.
  • Octreotide for example, is the synthetic octapeptide with sequence D-Phe-Cys-Phe- D-Trp-Lys-Thr-Cys-Thr-ol (2-7 disulphide bridge) and is typically administered as an acetate salt.
  • This SST-14 derivative retains the key Phe-(D)Trp-Lys-Thr ⁇ -turn required for in vivo SST-like activity but, in contrast to the natural hormone, has a terminal half-life of around 1.7 hours.
  • Octreotide is used in treatment of conditions including carcinoid tumours and acromegaly, and is typically administered over a sustained period of weeks, or more commonly many months or years.
  • Somatostatin receptor agonists are of particular interest for the treatment of many different types of cancers since a wide variety of tumours are found to express somatostatin receptors (SSTRs).
  • SSTRs somatostatin receptors
  • SSTR1-SSTR5 The most investigated somatostatin receptor agonists, including octreotide, show high selectivity for SSTR2 and SSTR5; thus, octreotide is of particular interest for the treatment of tumours expressing these types of receptors.
  • Octreotide The most common “simple" formulation of Octreotide is "Sandostatin” (RTM) from Novartis. This is an aqueous solution for subcutaneous (s.c) injection, and a 100 ⁇ g dose reaches a peak concentration of 5.2 ng/ml at 0.4 hours post injection. The duration of action can be up to 12 hours but s.c. dosing is generally carried out every 8 hours. Evidently, s.c. injection 3 times daily for periods of months or years is not an ideal dosing regime.
  • RTM Sandostatin
  • Pasireotide LAR is a long acting formulation of pasireotide which addresses some of the above issues.
  • Carcinoid tumours are intestinal tumour arising from specialised cells with paracrine functions (APUD cells). The primary tumour is commonly in the appendix, where it is clinically benign. Secondary, metastatic, intestinal carcinoid tumours secrete excessive amounts of vasoactive substances, including serotonin, bradykinin, histamine, prostaglandins, and polypeptide hormones.
  • carcinoid syndrome a syndrome of episodic cutaneous flushing, cyanosis, abdominal cramps, and diarrhea in a patient with valvular heart disease and, less commonly, asthma and arthropathy. These tumours may grow anywhere in the gastrointestinal tract (and in the lungs) with approximately 90% in the appendix. The remainder occurs in the ileum, stomach, colon or rectum.
  • treatment of carcinoid syndrome starts with i.v. bolus injection followed by i.v. infusion.
  • a depot formulation of octreotide formulated in ploy lactic-co-glycolic acid (PLGA) microspheres is started. However, during the first two weeks or more after injection of the depot, daily s.c. injections with octreotide are recommended to compensate for the slow release from the PLGA spheres.
  • PLGA lactic-co-glycolic acid
  • Certain of the pre-formulations of the present invention contain salts of one or more somatostatin receptor agonists (which are preferred examples of the peptide actives, which in turn are intended by any reference to "active agents” herein).
  • SST-14 is a peptide hormone
  • typical somatostatin receptor agonists will be peptides, especially of 14 or fewer amino acids.
  • Preferably such peptides will be structurally constrained such as by being cyclic and/or having at least one intra-molecular crosslink. Amide, ester or particularly disulphide crosslinks are highly suitable.
  • Preferred constrained peptides will exhibit a type-2 ⁇ turn. Such a turn is present in the key region of somatostatin.
  • Peptides may contain only amino acids selected from those 20 a-amino acids indicated in the genetic code, or more preferably may contain their isomers and other natural and non-natural amino acids, (generally ⁇ , ⁇ or ⁇ , L- or D- amino acids) and their analogues and derivatives.
  • the term "somatostatin receptor agonist" as used herein may optionally also encompass SST-14 and/or SST-28, since these are viable peptide actives when formulated as salts in the very high
  • Amino acid derivatives and amino acids not normally used for protein synthesis are especially useful at the termini of the peptides, where the terminal amino or carboxylate group may be substituted by or with any other functional group such as hydroxy, alkoxy, ester, amide, thio, amino, alkyl amino, di- or tri-alkyl amino, alkyl (by which is meant, herein throughout Ci-Cis alkyl, preferably Ci-Cs alkyl e.g.
  • aryl e.g phenyl, benzyl, napthyl etc
  • other functional groups preferably with at least one heteroatom and preferably having no more than 10 atoms in total, more preferably no more than 6.
  • somatostatin receptor agonists are constrained peptides of 6 to 10 a-amino acids, of which particular examples include octreotide, lanreotide (of sequence NH 2 -(D)Naph-Cys-Tyr-(D)Trp-Lys-Val-Cys-Thr-CONH 2 and its cyclic derivative of sequence NH 2 -(D)Naph-Cys-Tyr-(D)Phe-Lys-Val-Cys-Thr-CONH 2 both having a Cys-Cys intramolecular disulphide crosslink), pasireotide (aka SOM 230) and vapreotide.
  • octreotide of sequence NH 2 -(D)Naph-Cys-Tyr-(D)Trp-Lys-Val-Cys-Thr-CONH 2 and its cyclic derivative of sequence NH 2 -(D)Na
  • the somatostatin receptor agonist When present, the somatostatin receptor agonist will generally be formulated as 0.1 to 12% by weight of the total formulation (based on the amount of free base). Typical values will be 0.1 to 10%>, 0.5 to 9%>, preferably 1 to 8%> and more preferably 1 to 7%. A somatostatin receptor agonist content of 2-6 % is most preferable.
  • Doses of the somatostatin receptor agonist suitable for inclusion in the formulation, and thus the volume of formulation used, will depend upon the release rate (as controlled, for example by the solvent type and amount use) and release duration, as well as the desired therapeutic level, the activity and the rate of clearance of the particular active chosen.
  • an amount of 1 to 500 mg per dose would be suitable for providing a therapeutic level for between 7 and 90 days. This will preferably be 5 to 300 mg.
  • the level will typically be around 10 to 180 mg (e.g. for a 30 to 90 day duration).
  • the amount of octreotide will be around 0.2 to 3 mg per day between injections.
  • a depot administered every 30 days would have 6 to 90 mg or a 90 day depot have 18 to 270 mg of octreotide.
  • the dosage would typically be an amount of around 0.05 to 40 mg per week of depot duration, preferably 0.1 to 20 mg per week duration (e.g. 1 to 5 mg per week) for a duration of 1 to 24 weeks, preferably 2 to 16 (e.g. 3, 4, 8, 10 or 12) weeks.
  • the pre-formulation may be formulated for dosing weekly (e.g. every 7 ⁇ 1 days).
  • a total dose of 0.05 to 250 mg of Pasireotide per dose would be suitable for providing a therapeutic level for between 7 and 168 days. This will preferably be 0.1 to 200 mg, e.g. 0.2 to 150 mg, 0.1 to 100 mg, 20 to 160 mg etc.
  • a depot administered every 30 days might have, for example 0.2 to 20 mg of Pasireotide, or a 90 day depot might have 30 to 60 mg of Pasireotide.
  • salt of a peptide active agent such as an SRA
  • this will be a biologically tolerable salt.
  • Suitable salts include the acetate, pamoate, chloride or bromide salts. The chloride salt is most preferred.
  • such pre- formulations will not contain any somatostatin or a somatostatin analogue active agent. That is to say, an active agent is present which does not fall within the scope of somatostatin analogues described in the preceding section.
  • the pre-formulation may comprise an active agent which is not selected from endogenous somatostatins, SST-14, SST-28, octreotide, lanreotide, vapreotide or pasireotide or salts thereof. These peptides are preferably excluded from the pre-formulations of this embodiment. It is preferred that the pre- formulation is free of somatostatins, somatostatin receptor agonists and somatostatin analogues.
  • active agents which may be contained in pre-formulations of the invention include:
  • GLP-1 and analogues thereof e.g. GLP- 1(7-37), GLP- 1(7-36) amide, liraglutide, semaglutide, exenatide, and lixisenatide (AVE0010);
  • GLP-2 glucagon-like peptide 2 agonists
  • ZP1846 glucagon-like peptide 2 agonists
  • DPPIV inhibitors sodium/glucose cotransporter 2 (SGLT2) inhibitors.
  • Other peptides suitable for the invention include: angiopeptin, angiotensin I, II, III, antileukinate, anti-inflammatory peptide 2, aprotinin, bradykinin, bombesin, calcitonin, calcitriol, cholecystokinin (CCK), colony-stimulating factor,
  • corticotropin-releasing factor corticotropin-releasing factor, C-Peptide, DDAVP, dermorphin-derived tetrapeptide (TAPS), dynorphin, endorphins, endostatin, endothelin, endothelin-1, enkephalins, epidermal growth factor, erythropoietin, fibroblast growth factor, follicle stimulating hormone, follistatin, follitropin, galanin, galanin-like peptide, galectin-1, gastrin, gastrin-releasing peptide, G-CSF, ghrelin, glial-derived neurotrophic factor, GM- CSF, granulocyte colony-stimulating factor, growth hormone, growth hormone- releasing factor, hepatocyte growth factor, insulin, insulin-like growth factors-I and I, interferons, interleukins, leptin, leukemia inhibitory factor, melanocortin 1, 2, 3, 4, melanocyte-sti
  • Buprenorphine is also used for maintenance treatment of opioid addiction as well as potentially also cocaine and amphetamine and met-amphetamine addiction, where current sublingual buprenorphine formulations suffer from low bioavailability, high variability and limited effect duration, resulting in issues with unpredictable dose response and withdrawal symptoms, particularly in mornings.
  • opioid antagonists can be used for treating addiction using a convenient injection depot system as provided by the invention. Suitable opiate antagonists for use with the invention are naloxone, nalmefene, and naltrexone.
  • Antipsychotics including risperidone, iloperidone, paliperidone, olanzapine, asenapine, ziprazidone and aripiprazole are also highly suitable for the invention in view of the potential for improved treatment compliance by patients, as well as by providing stable plasma levels over time.
  • the invention is useful in the treatment of dementia, Alzheimer's disease and Parkinson's disease, which adversely affect cognition.
  • Suitable active ingredients include donepezil, rivastigmine, galantamine, and emantine, rasagilin and pramipexol.
  • 5HT 3 antagonists Another group of active agents which may be contained in pre- formulations of the invention are 5HT 3 antagonists.
  • the active agent comprises a 5HT 3 antagonist or second generation 5HT 3 antagonist, this is preferably selected from ondansetron, tropisetron, granisetron, dolasetron, palonosetron, alosetron, cilansetron and/or ramosetron or mixtures thereof.
  • Doses of the 5HT 3 antagonist suitable for inclusion in the formulation, and thus the volume of formulation used will depend upon the release rate (as controlled, for example by the solvent type and amount use) and release duration, as well as the desired therapeutic level, the activity of the specific agent, and the rate of clearance of the particular active chosen.
  • an amount of 1 to 500 mg per dose would be suitable for providing a therapeutic level for between 5 and 90 days. This will preferably be 1 to 300 mg. For granisetron, the level will typically be around 10 to 180 mg (e.g. for a 3 to 60 day duration).
  • the amount of granisetron will be around 0.2 to 3 mg per day between injections, for depots designed for release over 30 days to 1 year, preferably 3 to 6 months.
  • the stability of the active and linearity of the release rate will mean that the loading to duration may not be a linear relationship.
  • a depot administered every 30 days might have, for example 2 to 30 mg or a 90 day depot have 6 to 90 mg of active.
  • the pre-formulation comprises at least one active agent which is not a somatostatin receptor agonist.
  • the pre-formulation is free from somatostatin receptor agonists.
  • the pre-formulation may be free of an active agent which interacts as either agonist or antagonist at any of the SST(l) to SST(5) receptors (particularly in humans).
  • pre-formulation is a pharmaceutical composition, preferably is a parenteral pharmaceutical composition, more preferably is an injectable parenteral pharmaceutical composition, even more preferably is an injectable parenteral pharmaceutical composition for subcutaneous or intra-muscular application, even more preferably is an injectable parenteral pharmaceutical composition for subcutaneous application.
  • compositions do not include fragmentation agents, such as polyethyleneoxide or poly(ethylene glycol) (PEG) fragmentation agent, e.g. a PEG grafted lipid and/or surfactant.
  • fragmentation agents such as polyethyleneoxide or poly(ethylene glycol) (PEG) fragmentation agent, e.g. a PEG grafted lipid and/or surfactant.
  • compositions preferably do not include fragmentation agents such as Polysorbate 80 (P80), or other Polysorbates (e.g. Polysorbate 20), PEGylated phospholipids (PEG-lipids such as DSPE-PEG(2000), DSPE-PEG(5000), DOPE- PEG(2000) and DOPE-PEG(5000)), Solutol HS 15, PEGylated fatty acids (e.g. PEG-oleate), block co-polymers such as Pluronic® F127 and Pluronic® F68, ethoxylated castor oil derivatives (e.g.
  • fragmentation agents such as Polysorbate 80 (P80), or other Polysorbates (e.g. Polysorbate 20), PEGylated phospholipids (PEG-lipids such as DSPE-PEG(2000), DSPE-PEG(5000), DOPE- PEG(2000) and DOPE-PEG(5000)), Solutol HS 15, PEGylated fatty acids (e.g. PEG-o
  • PEGylated glyceryl fatty acid esters such as TMGO-15 from Nikko Chemicals
  • PEGylated tocopherols such as d-alpha tocopheryl poly(ethylene glycol) 1000 succinate known as Vitamin E TPGS from Eastman.
  • the active agent as a powder may gain stability (both storage and in vivo stability) by certain stabilising additives.
  • Such additives include sugars (e.g. sucrose, trehalose, lactose etc.), polymers (e.g.
  • polyols such as carboxy methyl cellulose), amino acids (such as methionine, glutamate, lysine etc.), lipid-soluble acid components such as HC1, anionic lipids and/or surface active agents (such as dioleoyl phosphatidyl glycerol (DOPG), palmitoyloleoyl phosphatidylglycerol (POPG) and oleic acid (OA)).
  • DOPG dioleoyl phosphatidyl glycerol
  • POPG palmitoyloleoyl phosphatidylglycerol
  • OA oleic acid
  • Single-dose formats must remain stable and potent in storage prior to use, but are disposable after the single use. It is a remarkable finding that non-aqueous pre- formulations comprising an alkylammonium EDTA salt have enhanced storage stability at elevated temperatures, such as at 25 °C or even 40°C. This offers advantages in terms of ease of transportation and storage (no need for refrigeration). It is preferred that a single dose format has a stability such that after storage for 2 months at 25 °C (with air in head space), the assayed active agent concentration is at least 95% that of the initial assayed active agent concentration, and after 3 months, the assayed active agent concentration is at least 90% that of the initial assayed active agent concentration.
  • a single dose format has a stability such that after storage for 2 months at 40°C (with air in head space), the assayed active agent concentration is at least 85% that of the initial assayed active agent concentration, and after 3 months, the assayed active agent concentration is at least 80% that of the initial assayed active agent concentration.
  • Multi-dose formats must not only remain stable and potent in storage prior to use, but must also remain stable, potent and relatively/effectively free of bacteria over the multiple-dose use regimen administration period after the first use in which a seal has been compromised. For this reason multi-dose formats often require an antimicrobial or microbial- static agent, e.g. bacteriostatic agent, preservative.
  • an antimicrobial or microbial- static agent e.g. bacteriostatic agent
  • antimicrobial or microbial- static agent which includes bacteriostatic agents and preservative.
  • bacteriostatic agents include benzalkonium chloride, m-cresol, benzyl alcohol or other phenolic preservatives. Typical concentrations as known in the art can be used.
  • components i) including components a) and c), components b) and d) being optional) and ii) will, where present at all, preferably be present in an amount of 0 to 5% (e.g. 0.01% to 5%) by weight, preferably no more than 2% by weight and more preferably no more than 1% by weight.
  • 0 to 5% e.g. 0.01% to 5%
  • components a) and b) make up at least 95% of the lipid components of the pre-formulations.
  • at least 99% of the total lipid content of the pre- formulation consists of components a) and b).
  • the lipid component of the pre-formulation consists essentially of components a) and b).
  • the pre-formulations of the present invention are generally formulated to be administered parenterally.
  • This administration will generally not be an intravascular method but will preferably be subcutaneous (s.c), intracavitary or intramuscular (i.m.).
  • the administration will be by injection, which term is used herein to indicate any method in which the formulation is passed through the skin, such as by needle, catheter or needle-less (needle-free) injector. It is, however, possible to take advantage of the high loading and other beneficial characteristics of the present formulation in non-parenteral applications, including topical or systemic application to skin, mucous membranes, nasal, buccal and/or oral cavities.
  • such non-parenteral administration is for topical use.
  • Preferred parenteral administration is by i.m or s.c. injection, most preferably by deep s.c. injection.
  • An important feature of the composition of the invention is that it can be administered both by i.m. and s.c. and other routes without toxicity or significant local effects. It is also suitable for intracavital administration.
  • the deep s.c. injection has the advantage of being less deep and less painful to the subject than the (deep) i.m. injection used for some current depots and is technically most suitable in the present case as it combines ease of injection with low risk of local side effects. It is a surprising observation of the present inventors that the formulations provide sustained release of active agent over a predictable time period by both subcutaneous and intramuscular injection. This therefore allows the site of injection to be varied widely and allows the dose to be administered without detailed consideration of the tissue depth at the site of injection.
  • the lipid pre- formulations of the present invention provide non- lamellar liquid crystalline depot compositions upon exposure to aqueous fluids, especially in vivo.
  • non- lamellar is used to indicate a normal or reversed liquid crystalline phase (such as a cubic or hexagonal phase) or the L3 phase or any combination thereof.
  • liquid crystalline indicates all hexagonal, all cubic liquid crystalline phases and/or all mixtures thereof.
  • Hexagonal as used herein indicates "normal” or “reversed” hexagonal (preferably reversed) and "cubic” indicates any cubic liquid crystalline phase unless specified otherwise.
  • compositions having appropriate phase behaviour are in the region of 40:60 to 70:30, preferably 45:55 to 55:45 and more preferably 40:60 to 54:46.
  • ratio of components a:b are in the region of 40:60 to 70:30, preferably 45:55 to 55:45 and more preferably 40:60 to 54:46.
  • Ratios of around 50:50 e.g. 49:51 to 51 :49 are highly preferred, most preferably around 50:50.
  • the pre-formulations of the present invention are of low viscosity. As a result, these pre-formulations must not be in any bulk liquid crystalline phase since all liquid crystalline phases have a viscosity significantly higher than could be administered by syringe or similar injecting dispenser.
  • the pre-formulations of the present invention will thus be in a non-liquid crystalline state, such as a solution, L 2 or L 3 phase, particularly solution or L 2 .
  • the L 2 phase as used herein throughout is preferably a "swollen" L 2 phase containing greater than 5 wt%, preferably greater than 7 %, and most preferably greater than 9% of organic mono-alcoholic solvent (component c) having a viscosity reducing effect.
  • the pre-formulations described herein are preferably of "low viscosity". This may be indicated, for example by the ability to be dispensed from a 1 ml disposable syringe through a small gauge needle.
  • the low viscosity mixtures can be dispensed through a needle of 19 awg, preferably smaller than 19 gauge, more preferably 23 awg (or most preferably even 27 gauge) needle by manual pressure.
  • the low viscosity mixture should be a mixture capable of passing through a standard sterile filtration membrane such as a 0.22 ⁇ syringe filter.
  • a typical range of suitable viscosities for the pre- formulations of the invention would be, for example, 1 to 1000 mPas, preferably 10 to 800 mPas, more preferably 50 to 750 mPas and most preferably 50 to 600 mPas at 20°C.
  • phase structure transition from a low viscosity mixture to a high viscosity (generally tissue adherent) depot composition.
  • a phase structure transition from a molecular mixture, swollen L 2 and/or L 3 phase to one or more (high viscosity) liquid crystalline phases such as normal or reversed hexagonal or cubic liquid crystalline phases or mixtures thereof.
  • Further phase transitions may also take place following administration. Obviously, complete phase transition is not necessary for the functioning of the invention but at least a surface layer of the administered mixture will form a liquid crystalline structure.
  • this transition will be rapid for at least the surface region of the administered formulation (that part in direct contact with air, body surfaces and/or body fluids). This will most preferably be over a few seconds or minutes (e.g. from 1 second up to 30 minutes, preferably up to 10 minutes, more preferably 5 minutes of less). The remainder of the composition may change phase to a liquid crystalline phase more slowly by diffusion and/or as the surface region disperses.
  • the invention is not limited to formulations which undergo a phase change to a liquid crystalline structure upon administration.
  • a depot composition may be formed upon administration by other mechanisms not requiring the formation of a liquid crystalline phase.
  • the formation of a depot composition is not accompanied by a conversion to a liquid crystalline phase.
  • the pre-formulations of the invention lose some or all of the organic solvent included therein (e.g. by diffusion) and take in aqueous fluid from the bodily environment (e.g. the in vivo environment).
  • the formulation preferably generates a non- lamellar, particularly liquid crystalline phase structure.
  • these non- lamellar structures are highly viscous and are not easily dissolved or dispersed into the in vivo environment. The result is a monolithic "depot" generated in vivo with only a limited area of exposure to body fluids.
  • the lipid depot is highly effective in solubilising and stabilising active agents such as peptides and protecting these from degradation mechanisms.
  • the active agent is gradually released and/or diffuses out from the composition. Since the environment within the depot composition is relatively protected, the pre-formulations of the invention are highly suitable for active agents with a relatively low biological half-life (see above).
  • the depot systems formed by the formulations of the present invention are highly effective in protecting the active agent from degradation and thus allow an extended release period.
  • the formulations of the invention thus may provide in vivo depots of peptide active agents which require administration only once every 5 to 90 days preferably 5 to 60 days, more preferably 6 to 32.
  • a longer stable release period is desirable for patient comfort and compliance, as well as demanding less time from health professionals if the composition is not to be self-administered.
  • patient compliance may be aided by a weekly (e.g. every 7 days, optionally ⁇ 1 day), bi-weekly (e.g. every 14 days, optionally ⁇ 2 days), or monthly (e.g.
  • depot precursors of the present invention are stable homogeneous phases. That is to say, they may be stored for considerable periods (preferably at least 6 months) at room or refrigerator temperature, without phase separation.
  • active agent e.g. Somatostatin analogue, e.g. octreotide
  • this allows for the dose of active agent (e.g. Somatostatin analogue, e.g. octreotide) to be selected by reference to the species, age, sex, weight, and/or physical condition of the individual subject, by means of injecting a selected volume.
  • the present invention thus provides for methods comprising the selection of a dosing amount specific to an individual, particularly by subject weight.
  • the means for this dose selection is the choice of administration volume.
  • the present invention provides a pre-formulation comprising a lipid mixture i) comprising components a), b), c), and optionally d), component ii), and 0-1.0% water.
  • a lipid mixture i) comprising components a), b), c), and optionally d), component ii), and 0-1.0% water.
  • the amounts of these components will typically be in the range 20-60% a), 20-60% b), 1-30% c) and 0.001-0.8% ii).
  • the pre-formulations of the present invention are highly advantageous in that they are stable to prolonged storage in their final "administration ready” form. As a result, they may readily be supplied for administration either by health professionals or by patients or their carers, who need not be fully trained health professionals and may not have the experience or skills to make up complex preparations. This is particularly important in long-duration, slow-effecting diseases such as diabetes.
  • the present invention provides a disposable administration device (which is also to include a device component) pre-loaded with a measured dose of a pre-formulation of the present invention.
  • a disposable administration device (which is also to include a device component) pre-loaded with a measured dose of a pre-formulation of the present invention.
  • a device will typically contain a single dose ready for administration, and will generally be sterile-packed such that the composition is stored within the device until administration.
  • Suitable devices include cartridges, ampoules and particularly syringes and syringe barrels, either with integral needles or with standard (e.g. luer) fittings adapted to take a suitable disposable needle. Kits
  • kits for the administration of at least one active agent, said kit containing a measured dose of a formulation of the invention and optionally an administration device or component thereof.
  • the dose will be held within the device or component, which will be suitable for i.m. or preferably s.c. administration.
  • the kits may include additional administration components such as needles, swabs, etc. and will optionally and preferably contain instructions for administration. Such instructions will typically relate to
  • the invention provides for a pre-filled administration device as indicated herein and a kit as indicated herein comprising a pre-formulation as described herein.
  • the "kit” may contain at least two vessels, a first containing a low viscosity mixture of i) a lipid mixture comprising components a), c) and optionally b), and ii), as described here, and a second containing a measured dose of at least one active agent d) as described herein.
  • Such a "two component kit” may comprise the active agent d) as a powder formulation in one vial or pre-filled syringe and components i) and ii) in a second vial or pre-filled syringe.
  • the pre-filled syringes before injection, the pre-filled syringes are connected and the powder comprising active agent is mixed with the matrix formulation by moving the syringe barrels back and forth, forming a solution or suspension which is injected.
  • the liquid lipid formulation is drawn from one vial, or is pre-filled into a syringe, and is injected into a vial containing powdered active agent (e.g. peptide).
  • This formulation may subsequently be mixed by hand shaking or other suitable reconstitution method (e.g. vortex mixing etc.).
  • the solvent component may be present in either or both vessels (e.g. vials or syringes). Where the solvent is at least partially constituted with the active agent, this will generally be in the form of a solution or suspension.
  • the invention therefore provides a two component kit comprising
  • an antioxidant component ii) optionally in a third vessel, preferably in the second vessel, or most preferably in the first vessel;
  • At least one syringe (which may be one or both of said first and
  • a needle for administration such as those described herein;
  • mixtures e.g. pre-formulations
  • the mixtures may have one or more of the following preferred features independently or in combination:
  • Component a) comprises, consists essentially of or preferably consists of GDO;
  • Component b) comprises, consists essentially of or preferably consists of soy PC;
  • Component c) comprises, consists essentially of or preferably consists of a 1, 2, 3 or 4 carbon alcohol, preferably isopropanol or more preferably ethanol;
  • Component c) includes a polar co-solvent such as propylene glycol;
  • the pre-formulation does not contain any somatostatin analogue (as described herein);
  • the pre-formulation has a low viscosity as indicated herein;
  • the pre-formulation forms a non-lamellar liquid crystalline phase as indicated herein upon in vivo administration
  • the pre-formulation generates a depot following in vivo administration, which depot releases at least one active agent at a therapeutic level over a period of at least 7 days, preferably at least 21 days, more preferably at least 28 days;
  • the method(s) of treatment of the present invention may have one or more of the following preferred features independently or in combination;
  • the method comprises the administration of at least one formulation with one or more preferred features as indicated above;
  • the method comprises the administration of at least one formulation as indicated herein by i.m., s.c. (e.g. deep s.c.) injection;
  • the method comprises administration by means of a pre-filled administration device as indicated herein;
  • the method comprises administration through a needle no larger than 20 gauge, preferably smaller than 20 gauge, and most preferably 22 gauge, 23 gauge or smaller;
  • the method comprises a single administration every 5 to 90 days, preferably 6 to 32 days (for example 7 days or 28-31 days);
  • the use(s) of the pre-formulations indicated herein in the manufacture of medicaments may have one or more of the following preferred features independently or in
  • the use comprises the use of at least one formulation with one or more preferred features as indicated above;
  • the use comprises the manufacture of a medicament for administration of at least one formulation as indicated herein by i.m. or s.c. injection;
  • the use comprises the manufacture of a medicament for administration by means of a pre-filled administration device as indicated herein;
  • the use comprises the manufacture of a medicament for administration through a needle no larger than 20 gauge, preferably smaller than 20 gauge, and most preferably 22 gauge, 23 gauge or smaller;
  • the use comprises the manufacture of a medicament for administration once every 5 to 90 days, preferably 5 to 60 days, more preferably 6 to 32 days;
  • the pre- filled devices of the invention may have one or more of the following preferred features independently or in combination:
  • They comprise a needle smaller than 20 gauge, preferably no larger than 22 gauge or no larger than 23 gauge;
  • compositions of the invention contain a homogeneous mixture of a composition of the invention in ready-to- inject form.
  • They contain a formulation of components i) (preferably comprising a), b) and c)) and ii) for combination with an active agent.
  • They contain a total volume for administration of no more than 5 ml, preferably no more than 3 ml more preferably no more than 1.5 ml.
  • kits of the invention may have one or more of the following preferred features
  • They contain a needle smaller than 20 gauge, preferably no larger than 22 gauge or no larger than 23 gauge;
  • They contain a total volume for administration of no more than 5 ml, preferably no more than 3 ml more preferably no more than 1.5 ml;
  • EDTA(Na) and alkylamine into glass vials, e.g. 15R vials, followed by addition of organic solvent or solvent mixture (e.g EtOH/PG (50/50 w/w)).
  • organic solvent or solvent mixture e.g EtOH/PG (50/50 w/w)
  • Vials were sealed and placed on either a roller mixer by end-over-end rotation at ambient RT or magnetic stirrer. During dissolution, vials were visually inspected for undissolved EDTA particles using ambient and cross-polarized light.
  • Samples were prepared by weighing the appropriate amount of FeCl3 x 6H 2 0 into sterilized glass vials followed by addition of organic solvent or solvent mixture. Vials were sealed and placed on a roller mixer by end-over-end rotation at ambient RT until FeCl3 x 6H 2 0 was completely dissolved.
  • Lipid placebo formulations were prepared by weighing appropriate amounts of SPC, GDO, EDTA/alkylamine solution, and FeCl3 x 6H 2 0 (when needed) solution into sterilized glass vials. The sealed vials were then placed on a roller mixer at room temperature until mixed completely into clear homogeneous liquid solution ( ⁇ 24 hours).
  • API-containing formulations were prepared by adding appropriate amounts of API powder to the lipid placebo formulations in sterilized glass vials. The vials were sealed and placed on a roller mixer at room temperature until mixed completely into clear homogeneous liquid solution (ca. 24 hours).
  • EDTA and ETA were dissolved in EtOH/PG (50/50 w/w) mixture. Then, appropriate amounts of SPC, GDO (at SPC/GDO weight ratio 50/50) and EtOH/PG/EDTA/ETA mixture were weighed into a sterilized 20R glass vial. The sealed vial was then placed on a roller mixer at room temperature until mixed completely into clear homogeneous liquid solution ( ⁇ 24 hours). OCT(Cl) powder was then added to the lipid formulations in sterilized 15R glass vial at 2.34 wt% concentration. The vial was sealed and placed on a roller mixer at room temperature until mixed completely into clear homogeneous liquid solution (24 hours).
  • lipid peptide (e.g. octreotide) formulations as above were divided into sterilized 2R glass vials (0.5 g of formulation per vial).
  • the head space of the vials was ambient air, i.e., no inert atmosphere such as nitrogen was introduced in the head space.
  • Vials were sealed and placed in controlled environment storage cabinets at 25°C/60% RH and 40°C/75% RH.
  • At predefined sampling points (up to three months of storage) two vials of each formulation and storage cabinet were withdrawn, equilibrated to room temperature for 1 hour and analyzed for peptide content (assay) using gradient HPLC with UV detection. It should be noted that the filling procedure and storage conditions ensured forced degradation conditions as the head space was composed of air rather than inert atmosphere such as nitrogen.
  • peptide e.g. octreotide, such as octreotide chloride
  • lipid formulations were carried out by gradient HPLC with UV detection.
  • the HILIC analytical column used was a HALO Penta-HILIC 2.7 ⁇ , 150 ⁇ 3.0 mm.
  • Quantification was carried out by interpolating the peptide (e.g. octreotide) peak area obtained in lipid formulation samples (prepared by dissolving the lipid formulation in a sample solvent at the required target peptide concentration) into the calibration curves generated from standard solutions containing known
  • peptide e.g. octreotide
  • a typical mobile phases used (for example with octreotide) consisted of water: 2M sodium chloride: acetonitrile: trifluoroacetic acid 384: 16:400: 1 (v/v) (mobile phase A) and water: methanol: acetonitrile: trifluoroacetic acid 20:30:950: 1 (v/v) (mobile phase B).
  • the detection was carried out at 220 nm.
  • the sample solvent used was acetonitrile: methanol (1 : 1, v/v); octreotide eluted after approximately 25.2 min.
  • results are also in some cases expressed as a Stability Index for API assay.
  • the Stability Index is calculated as the API assay value in the particular formulation divided by the API assay value in the reference formulation. Expressed in this way, Stability Index values greater than 1 means improved API stability when compared to the reference formulation.
  • Oxygen concentration in the vial headspace was measured using a PC-controlled PreSens Microx TX3 micro fiber optic oxygen transmitter equipped with a needle- type optical oxygen microsensor (NTH, 140 ⁇ flat broken tip). Measurements were performed by penetrating the oxygen microsensor through the vial rubber stopper into the vial headspace and measuring the oxygen concentration until a stable readout was obtained (about 1 min).
  • EDTA and EDTA(Na) solutions in EtOH/PG were prepared in the presence and absence of ETA (Table 1). Dissolution of EDTA and EDTA(Na) during end-over-end rotation at ambient RT was assessed by visual inspection (ambient and crossed-polarized light) over 27 days. The results show that neither the disodium salt (EDTA(Na)) nor the acid form of EDTA is soluble in EtOH/PG without using ETA even after 27 days of mixing.
  • Table 2 summarizes results on EDTA solubility at a concentration of 0.38 wt% in EtOH/PG solvent mixtures (1/1 wt/wt) as a function of ETA/EDTA molar ratio. The only sample where EDTA was not fully dissolved was for the lowest ETA/EDTA molar ratio. In all other samples EDTA was soluble after 24 h end-over-end rotation mixing at ambient RT. The obtained results show that about 3.5 mol of ETA per 1 mol of EDTA is close to the required minimum amount needed to solubilize EDTA in the non-aqueous solvent used. Table 2. Solubility of 0.38 wt% EDTA in EtOH/PG as a function of ETA/EDTA molar ratio.
  • Table 3 summarizes EDTA solubility results in EtOH/PG (1/1 wt/wt) solvent mixture at 0.38 wt% EDTA as a function of DiETA EDTA molar ratio after 24 h end-over-end rotation mixing at ambient RT.
  • the obtained results show that about 4.5 mol of DiETA per 1 mol of EDTA is close to the required minimum amount needed to solubilize EDTA in non-aqueous solvent used.
  • Table 4 summarizes EDTA solubility results in EtOH/PG (1/1 wt/wt) solvent mixture at 0.38 wt% EDTA as a function of ethylenediamine/EDTA molar ratio after 24 h end-over-end rotation mixing at ambient RT.
  • the obtained results showed that about 2.5 mol of ethylenediamine per 1 mol of EDTA is close to the required minimum amount needed to solubilize EDTA in non-aqueous solvent used.
  • Table 5 summarizes EDTA solubility results in EtOH/PG (1/1 wt/wt) solvent mixture at 0.38 wt% EDTA as a function of serinol/EDTA molar ratio after 24 h end-over-end rotation mixing at ambient RT.
  • the obtained results showed that about 4 mol of serinol per 1 mol of EDTA is close to the required minimum amount needed to solubilize EDTA in non-aqueous solvent used.
  • Table 6 summarizes EDTA solubility results in EtOH/PG (1/1 wt/wt) solvent mixture at 0.38 wt% EDTA as a function of TRIS/EDTA molar ratio after 7 days end-over-end rotation mixing at ambient RT. The obtained results showed that about 5 mol of TRIS per 1 mol of EDTA is close to the required minimum amount needed to solubilize EDTA in non-aqueous solvent used.
  • Lipid formulations containing 2.34 wt% of OCT(Cl) in the presence and absence of 100 ppm of EDTA were prepared according to the compositions given in Table 7. Formulations were divided into sterilized 2R glass vials (0.5 g of formulation per vial), sealed and placed in controlled environment storage cabinets at either
  • the headspace of the vials was ambient air to ensure forced degradation conditions, i.e., no inert atmosphere such as nitrogen was introduced.
  • forced degradation conditions i.e., no inert atmosphere such as nitrogen was introduced.
  • two vials of each formulation and storage condition were withdrawn from the controlled environment cabinets, equilibrated to room temperature for 1 hour and analyzed for peptide content (assay) using gradient HPLC with UV detection.
  • Figure 1 presents the octreotide assay at different storage time points and storage conditions. As shown in Figure 1, the presence of 0.01 wt% (100 ppm) of EDTA solubilized in the lipid formulation by the use of 0.01 wt% (100 ppm) ETA dramatically enhanced the peptide stability at both storage conditions.
  • Lipid formulations containing 2.27 wt% of OCT(Cl) and different concentrations of EDTA were prepared according to the compositions given in Table 8.
  • Formulations were divided into sterilized 2R glass vials (0.5 g of formulation per vial), sealed and placed in controlled environment storage cabinets at either 40°C/75% RH or 25°C/60% RH.
  • the head space of the vials was ambient air to ensure forced degradation conditions, i.e., no inert atmosphere such as nitrogen was introduced.
  • two vials of each formulation and storage condition were withdrawn from the controlled environment cabinets, equilibrated to room temperature for 1 hour and analyzed for peptide content (assay) using gradient HPLC with UV detection.
  • Lipid formulations containing OCT(Cl) in the absence and presence of 100 ppm EDTA were prepared according to the compositions given in Table 9.
  • Formulations were divided into sterilized 1 mL 22G* l/2" glass syringes (Schott AG) (0.5 g of formulation per syringe), sealed with plunger and placed in a controlled environment storage cabinet at 25°C/60% RH.
  • two syringes of each formulation were withdrawn from the controlled environment cabinet, equilibrated to room temperature for 1 hour and analyzed for peptide content (assay) using gradient HPLC with UV detection.
  • Table 9 Table 9.
  • OCT(Cl) containing lipid formulation compositions (in wt%) without and with EDTA OCT(Cl) containing lipid formulation compositions (in wt%) without and with EDTA.
  • the octreotide content corresponds to 20 mg/mL octreotide free base when corrected for peptide content, purity and formulation density.
  • Figure 3 presents the octreotide assay at different storage time points. As shown, the presence of 0.01 wt% (100 ppm) of EDTA solubilized in the lipid formulation with the help of ETA significantly enhanced the long-term peptide stability in pre-filled syringes at the long-term 25°C/60% RH storage condition.
  • EXAMPLE 10 Stability of OCT(Cl) in lipid formulations in the presence of iron and EDTA
  • Lipid formulations containing OCT(Cl) and different amounts of Fe 3+ and EDTA were prepared according to the compositions given in Table 10.
  • Formulations were divided into sterilized 2R glass vials (0.5 g of formulation per vial), sealed and placed in a controlled environment storage cabinet at 40°C/75% RH. The head space of the vials was ambient air to ensure forced degradation conditions, i.e., no inert atmosphere such as nitrogen was introduced.
  • 2R glass vials 0.5 g of formulation per vial
  • the head space of the vials was ambient air to ensure forced degradation conditions, i.e., no inert atmosphere such as nitrogen was introduced.
  • At 1 -month sampling point two vials of each formulation and storage condition were withdrawn from the controlled environment cabinet, equilibrated to room temperature for 1 hour and analyzed for peptide content (assay) using gradient HPLC with UV detection.
  • OCT(Cl) containing FluidCrystal formulation compositions (in wt%) with different concentrations of Fe 3+ and EDTA.
  • the octreotide content corresponds to 20 mg/mL octreotide free base when corrected for peptide content, purity and formulation density.
  • the SPC/GDO weight ratio is 50/50 in all formulations.
  • Figure 4 presents the octreotide assay at 1 -month time point as a function of Fe concentration in the presence of different amounts of EDTA.
  • Fe 3+ concentration As evident, with increasing the Fe 3+ concentration, more EDTA is needed to protect OCT from degradation. The protection against OCT degradation in the presence of Fe 3+ is enhanced with increasing EDTA concentration up to 100 ppm, followed by some decline between 100 and 250 ppm. There is also a clear correlation between Fe 3+ concentration and amount of EDTA needed to suppress the catalytic activity of iron.
  • a maximum stabilization effect is achieved starting from EDTA:Fe molar ratio of about 2:1. This corresponds to about 100 ppm EDTA at a Fe content of 10 ppm.
  • EXAMPLE 11 Stability of OCT(Cl) in lipid formulations with EDTA and iron in the absence and presence of ETA
  • Lipid formulations containing EDTA or EDTA(Na) in the absence and presence of ETA were prepared according to the compositions given in Table 1 1. As shown in Example 1 , neither EDTA(Na) nor EDTA are soluble in EtOH/PG without using ETA. EDTA(Na) was also insoluble in EtOH/PG even in the presence of ETA as assessed by visual inspection. Therefore, EDTA(Na), EDTA and EDTA(Na)/ETA containing mixtures in EtOH/PG were additionally filtered using a Millex-LG hydrophilic PTFE 0.2 ⁇ syringe filter to remove the non-dissolved EDTA particles.
  • formulations were divided into sterilized 2R glass vials (0.5 g of formulation per vial), sealed and placed in a controlled environment storage cabinet at 40°C/75% RH.
  • the headspace of the vials was ambient air to ensure forced degradation conditions, i.e., no inert atmosphere such as nitrogen was introduced.
  • forced degradation conditions i.e., no inert atmosphere such as nitrogen was introduced.
  • the octreotide content corresponds to 20 mg/mL octreotide free base when corrected for peptide content, purity and formulation density.
  • the SPC/GDO weight ratio was 50/50 in all formulations.
  • EDTA mixtures in EtOH/PG were filtered using Millex-LG hydrophilic PTFE 0.2 ⁇ syringe filter to remove insoluble EDTA particles.
  • ** 0.00242 wt% of FeCl 3 x6H 2 0 corresponds to 5 ppm of Fe 3+ .
  • Figure 6 presents the assay and Stability Index values of octreotide as a function of time, respectively.
  • EDTA solubilized in the lipid formulation with the help of ETA dramatically enhanced the peptide stability compared to the reference formulation in the presence of 5 ppm Fe .
  • EXAMPLE 12 Effect of different alkylamines and solvents on stability of OCT(Cl) in lipid formulations with EDTA
  • Lipid formulations were prepared according to the compositions given in Table 12. Formulations were divided into sterilized 2R glass vials (0.5 g of formulation per vial), sealed and placed in a controlled environment storage cabinet at 40°C/75% RH. The headspace of the vials was ambient air to ensure forced degradation conditions, i.e., no inert atmosphere such as nitrogen was introduced. At predefined sampling points (up to two months of storage) two vials of each formulation and storage condition were withdrawn from the controlled environment cabinets, equilibrated to room temperature for 1 hour and analyzed for peptide content (assay) using gradient HPLC with UV detection.
  • OCT(Cl) containing lipid formulation compositions (in wt%).
  • the octreotide content corresponds to 20 mg/mL octreotide free base when corrected for peptide content, purity and formulation density.
  • the SPC/GDO weight ratio was 50/50 and ETA:EDTA, DiETA:EDTA and ethylenediamine:EDTA molar ratios were 4.T in all formulations.
  • Figure 7 presents the octreotide assay at different storage time points.
  • the different alkylamines (ETA, DiETA or ethylenediamine) used to solubilize 0.01 wt% (100 ppm) of EDTA into the lipid formulations enhanced the peptide stability to a similar high degree when compared to the reference formulation.
  • the obtained results also show that the positive effect of EDTA on the stability of OCT(CI) is independent on the mixture used to prepare the lipid formulations as indicated by the data for EtOH/PG containing formulations in Figure 8 when compared with Figure 9.
  • Lipid formulations containing SOM(Cl) in the absence and presence of 100 ppm EDTA using EtOH/PG were prepared according to the compositions given in Table 13. Formulations were divided into sterilized 2R glass vials (0.5 g of formulation per vial), sealed and placed in controlled environment storage cabinets at either
  • the head space of the vials was ambient air to ensure forced degradation conditions, i.e., no inert atmosphere such as nitrogen was introduced.
  • forced degradation conditions i.e., no inert atmosphere such as nitrogen was introduced.
  • two vials of each formulation and storage condition were withdrawn from the controlled environment cabinets, equilibrated to room temperature for 1 hour and analyzed for peptide content (assay) using gradient HPLC with UV detection.
  • Figure 9 presents the SOM assay at different storage time points and storage conditions. As shown, the presence of 100 ppm of EDTA solubilized in the lipid formulation by the use of ETA dramatically enhanced the peptide stability at both 40°C/75% RH and 25°C/60% RH storage conditions.
  • EXAMPLE 14 Stability of GOS(Cl) in lipid formulations in the presence of EDTA and iron
  • Lipid formulations containing GOS(Cl) in the absence and presence of 100 ppm EDTA were prepared according to the compositions given in Table 14. Formulations were divided into sterilized 2R glass vials (0.9 g of formulation per vial), sealed and placed in a controlled environment storage cabinet at 40°C/75% RH. The headspace of the vials was ambient air to ensure forced degradation conditions, i.e., no inert atmosphere such as nitrogen was introduced. Both formulations also contained 5 ppm Fe 3+ to ensure additional oxidative stress conditions. At predefined sampling points (up to two months of storage) two vials of each formulation were withdrawn from controlled environment cabinets, equilibrated to room temperature for 1 hour and analyzed for peptide content (assay) using gradient HPLC with UV detection.
  • Figure 10 presents the assay and Stability Index values of GOS as a function of time, respectively.
  • the use of 100 ppm EDTA solubilized in the lipid formulation with the help of ETA significantly enhanced the peptide stability in the presence of 5 ppm Fe 3+ .
  • the data indicate that EDTA provides protection of the peptide towards low to moderate levels of metals that may originate from the excipients, the API or the processing equipment.
  • EXAMPLE 15 Stability of OXY(Cl) in lipid formulations in the presence of EDTA and iron
  • Lipid formulations containing OXY(Cl) in the absence and presence of 100 ppm EDTA were prepared according to the compositions given in Table 15. Formulations were divided into sterilized 2R glass vials (0.9 g of formulation per vial), sealed and placed in a controlled environment storage cabinet at 40°C/75% RH. The headspace of the vials was ambient air to ensure forced degradation conditions, i.e., no inert atmosphere such as nitrogen was introduced. Both formulations also contained 5 ppm Fe 3+ to enhance the oxidative stress conditions.
  • Figure 11 presents the assay and Stability Index values of OXY as a function of time, respectively.
  • the use of 100 ppm EDTA solubiiized in the lipid formulation with the help of ETA significantly enhanced the peptide stability in the presence of 5 ppm Fe 3+ .
  • the data indicate that EDTA provides protection of the peptide towards low to moderate levels of metals that may originate from the excipients, the API or the processing equipment.
  • Lipid formulations containing GRN(0) in the absence and presence of 100 ppm EDTA were prepared according to the compositions given in
  • Formulations were divided into sterilized 2R glass vials (1 g of formulation per vial), sealed and placed in a controlled environment storage cabinet at 40°C/75% RH.
  • the headspace of the vials was ambient air to ensure forced degradation conditions, i.e., no inert atmosphere such as nitrogen was introduced.
  • Both formulations also contained 5 ppm Fe to ensure additional oxidative stress conditions.
  • At predefined sampling points (up to two months of storage) two vials of each formulation were withdrawn from the controlled environment cabinets, equilibrated to room temperature for 1 hour and analyzed for peptide content (assay) using gradient HPLC with UV detection.
  • GRN(O) containing lipid formulation compositions in wt%) without and with EDTA.
  • the GRN concentration is 9.94 mg/g in all formulations.
  • the SPC/GDO weight ratio is 50/50 in all formulations.
  • Figure 12 presents assay and Stability Index values of GRN as a function of time, respectively.
  • 100 ppm EDTA solubilized in the lipid formulation with the help of ETA significantly enhanced the stability of GRN in the presence of 5 ppm Fe .
  • the data indicate that EDTA provides protection of the active substance towards low to moderate levels of metals that may originate from the excipients, the API or the processing equipment.
  • Lipid formulations containing GOS(Cl) in the absence and presence of 100 ppm EDTA were prepared according to the compositions given in
  • Formulations were divided into sterilized 2R glass vials (1 g of formulation per vial), sealed and placed in controlled environment storage cabinet at 40°C/75% RH. The headspace of the vials was ambient air to ensure forced degradation conditions, i.e., no inert atmosphere such as nitrogen was introduced. All formulations also contained 5 ppm Fe 3+ to enhance the oxidative stress conditions. At predefined sampling points (up to 9 weeks of storage) two vials of each formulation were withdrawn from the controlled environment cabinets, equilibrated to room temperature for 1 hour and analyzed for peptide content (assay) using gradient HPLC with UV detection.
  • Figure 13 and Figure 14 present the assay and Stability Index values of GOS solubilized in either SPC/GMO or SPC/SbOil based formulations as a function of time, respectively.
  • 100 ppm EDTA solubilized in both formulation concepts with the help of ETA significantly enhanced the peptide stability in the presence of 5 ppm Fe 3+ .
  • the data indicate that EDTA provides protection of the peptide towards low to moderate levels of metals that may originate from the excipients, the API or the processing equipment.
  • Lipid placebo formulations in the absence and presence of 100 ppm EDTA were prepared according to the compositions given in Table 18.
  • Formulations were divided into sterilized 2R glass vials (1 g of formulation per vial), sealed and placed in controlled environment storage cabinets at either 60°C/ambient RH or 40°C/75% RH.
  • the headspace of the vials was ambient air to ensure forced lipid oxidation conditions, i.e., no inert atmosphere such as nitrogen was introduced.
  • Some formulations also contained 5 ppm Fe to enhance the oxidative stress conditions (Table 18).
  • Lipid formulation compositions (in wt%) without and with EDTA.
  • the SPC/GDO weight ratio was 50/50 and 35/65 in Samples 103-106 and Samples 107- 110, respectively.
  • 0.08 wt% DTPA solutions in EtOH/PG (50/50 w/w) were prepared in the absence and presence of various amounts of ETA added at different ETA/DTPA molar ratios (Table 19).
  • the results show that DTPA is not soluble in EtOH/PG without using ETA.
  • the obtained results also show that about 4.3 mol of ETA per 1 mol of DTPA is close to the required minimum amount needed to solubilize DTPA in the nonaqueous solvent used.
  • Table 19 Solubility of 0.08 wt% DTPA in EtOH/PG as a function of ETA/DTP A molar ratio.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Diabetes (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Endocrinology (AREA)
  • Hematology (AREA)
  • Immunology (AREA)
  • Dermatology (AREA)
  • Obesity (AREA)
  • Molecular Biology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biophysics (AREA)
  • Ophthalmology & Optometry (AREA)
  • Child & Adolescent Psychology (AREA)
  • Biomedical Technology (AREA)
  • Dispersion Chemistry (AREA)
  • Zoology (AREA)
  • Cell Biology (AREA)
  • Neurology (AREA)
  • Vascular Medicine (AREA)
  • Emergency Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne des mélanges qui comportent : i) au moins un lipide et/ou au moins une huile; ii) un sel d'EDTA de type alkylammonium, le mélange ayant une teneur en eau située dans une plage comprise entre 0 et 1,0 % en poids. L'invention concerne en outre des mélanges qui sont des pré-préparations, des méthodes de traitement comprenant l'administration de telles pré-préparations, des dispositifs d'administration pré-remplis et des nécessaires contenant les préparations, l'utilisation d'un sel d'EDTA de type alkylammonium pour ralentir la décomposition des composants lipidiques et/ou de tout agent actif contenu dans la pré-préparation, et des sels d'EDTA de type alkylammonium, ainsi que décrit dans la description.
PCT/EP2017/074418 2016-09-07 2017-09-26 Mélanges et préparations comportant un sel d'edta de type alkylammonium WO2018060212A1 (fr)

Priority Applications (13)

Application Number Priority Date Filing Date Title
CN201780059020.8A CN109789214B (zh) 2016-09-27 2017-09-26 包含edta烷基铵盐的混合物和制剂
KR1020197008819A KR102611788B1 (ko) 2016-09-27 2017-09-26 알킬 암모늄 edta 염을 포함하는 혼합물 및 제형
MX2019003520A MX2019003520A (es) 2016-09-27 2017-09-26 Mezclas y formulacions que comprenden una sal de alquil amonio de acido etilendiaminotetraacetico (edta).
IL265535A IL265535B (en) 2016-09-27 2017-09-26 Mixtures and formulations containing alkyl ammonium salt edta
AU2017336199A AU2017336199B2 (en) 2016-09-27 2017-09-26 Mixtures and formulations comprising an alkyl ammonium EDTA salt
US16/335,487 US11241476B2 (en) 2016-09-27 2017-09-26 Mixtures and formulations comprising an alkyl ammonium EDTA salt
JP2019516405A JP7138626B2 (ja) 2016-09-27 2017-09-26 アルキルアンモニウムｅｄｔａ塩を含む混合物及び製剤
RU2019110439A RU2775780C2 (ru) 2016-09-27 2017-09-26 Смеси и составы, содержащие алкиламмониевую соль эдта
EP17772707.0A EP3518978A1 (fr) 2016-09-27 2017-09-26 Mélanges et préparations comportant un sel d'edta de type alkylammonium
IL295457A IL295457A (en) 2016-09-27 2017-09-26 Mixtures and formulations containing alkyl ammonium salt edta
CA3038412A CA3038412A1 (fr) 2016-09-27 2017-09-26 Melanges et preparations comportant un sel d'edta de type alkylammonium
US17/586,014 US20220257694A1 (en) 2016-09-27 2022-01-27 Mixtures and formulations
US18/161,828 US20230285502A1 (en) 2016-09-07 2023-01-30 Mixtures and formulations

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP16190892.6 2016-09-27
EP16190892 2016-09-27
GB1616366.9 2016-09-27
GBGB1616366.9A GB201616366D0 (en) 2016-09-27 2016-09-27 Formulations

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US16/335,487 A-371-Of-International US11241476B2 (en) 2016-09-27 2017-09-26 Mixtures and formulations comprising an alkyl ammonium EDTA salt
US17/586,014 Continuation US20220257694A1 (en) 2016-09-07 2022-01-27 Mixtures and formulations

Publications (1)

Publication Number Publication Date
WO2018060212A1 true WO2018060212A1 (fr) 2018-04-05

Family

ID=59923462

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/EP2017/074418 WO2018060212A1 (fr) 2016-09-07 2017-09-26 Mélanges et préparations comportant un sel d'edta de type alkylammonium
PCT/EP2017/074420 WO2018060213A1 (fr) 2016-09-07 2017-09-26 Formulations contenant un agoniste du récepteur de la somatostatine

Family Applications After (1)

Application Number Title Priority Date Filing Date
PCT/EP2017/074420 WO2018060213A1 (fr) 2016-09-07 2017-09-26 Formulations contenant un agoniste du récepteur de la somatostatine

Country Status (11)

Country Link
US (5) US11241476B2 (fr)
EP (2) EP3518978A1 (fr)
JP (1) JP7138626B2 (fr)
KR (1) KR102611788B1 (fr)
CN (2) CN109789215B (fr)
AU (1) AU2017336199B2 (fr)
CA (1) CA3038412A1 (fr)
IL (2) IL265535B (fr)
MX (1) MX2019003520A (fr)
TW (2) TWI805558B (fr)
WO (2) WO2018060212A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10688148B2 (en) 2016-09-27 2020-06-23 Camurus Ab Formulations containing a somatostatin receptor agonist
WO2020240017A1 (fr) 2019-05-29 2020-12-03 Camurus Ab Compositions à libération contrôlée de lipides

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE602005008247D1 (de) * 2004-06-04 2008-08-28 Camurus Ab Flüssige depotformulierungen
TWI624271B (zh) * 2011-05-25 2018-05-21 凱慕路斯公司 包含低黏度混合物之預調配物及其形成方法，及該低黏度混合物或預調配物之用途
WO2020240018A1 (fr) 2019-05-29 2020-12-03 Camurus Ab Dispositif & régime d'administration

Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002356464A (ja) * 2001-05-30 2002-12-13 Showa Denko Kk 高純度アミノポリカルボン酸及びその塩と製造方法
WO2005014777A2 (fr) * 2002-10-16 2005-02-17 Board Of Regents, The University Of Texas System Procedes et compositions pour augmenter l'efficacite de substances actives d'un point de vue biologique
WO2005117830A1 (fr) 2004-06-04 2005-12-15 Camurus Ab Formulations de depot lipidique
WO2006075124A1 (fr) 2005-01-14 2006-07-20 Camurus Ab Formulations à base d'analogues de somatostatine
WO2006075123A1 (fr) 2005-01-14 2006-07-20 Camurus Ab Formulations bioadhesives topiques
WO2006131730A1 (fr) 2005-06-06 2006-12-14 Camurus Ab Formulations d'analogues de glp-1
WO2010020794A1 (fr) 2008-08-22 2010-02-25 Camurus Ab Préparations lipidiques comprenant un antioxydant thiolé
WO2012160213A1 (fr) 2011-05-25 2012-11-29 Camurus Ab Formulations peptidiques à libération contrôlée
WO2013083459A1 (fr) 2011-12-05 2013-06-13 Camurus Ab Formulations peptidiques robustes à libération contrôlée
WO2013174978A1 (fr) * 2012-05-25 2013-11-28 Camurus Ab Formulation d'agoniste des récepteurs à la somatostatine
WO2014016428A1 (fr) 2012-07-26 2014-01-30 Camurus Ab Formulations d'opioïdes
WO2016066655A1 (fr) 2014-10-27 2016-05-06 Camurus Ab Formulation injectable de buprénorphine
WO2016102683A1 (fr) 2014-12-23 2016-06-30 Camurus Ab Formulations à libération contrôlée

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5313357B2 (fr) 1974-05-07 1978-05-09
JPS5313357A (en) * 1976-07-22 1978-02-06 Toshiba Corp Formation of connector lead of semiconductor device
US5874105A (en) 1996-01-31 1999-02-23 Collaborative Laboratories, Inc. Lipid vesicles formed with alkylammonium fatty acid salts
JP2000509404A (ja) 1996-05-08 2000-07-25 ニカ ヘルス プロダクツ リミテッド 遺伝物質の導入システムとしてのカチオン性ヴィロソーム
WO2004091622A1 (fr) 2003-04-08 2004-10-28 Progenics Pharmaceuticals, Inc. Utilisation d'antagonistes des opioides peripheriques, en particulier de methylnaltrexone, dans le traitement du syndrome du colon irritable
GB0407908D0 (en) * 2004-04-07 2004-05-12 Univ York Ionic liquids
US8871712B2 (en) 2005-01-14 2014-10-28 Camurus Ab Somatostatin analogue formulations
AU2006256041B2 (en) 2005-06-10 2012-03-29 Chugai Seiyaku Kabushiki Kaisha Stabilizer for protein preparation comprising meglumine and use thereof
PL387296A1 (pl) 2009-02-17 2010-08-30 Instytut Farmaceutyczny Sposób aktywnego zamykania amfifilowych substancji czynnych w strukturach liposomowych
WO2012160212A1 (fr) 2011-05-25 2012-11-29 Camurus Ab Formulation de peptides à libération contrôlée
KR101586791B1 (ko) 2012-12-28 2016-01-19 주식회사 종근당 ＧｎＲＨ 유도체의 서방성 지질 초기제제 및 이를 포함하는 약제학적 조성물
WO2016094662A1 (fr) * 2014-12-10 2016-06-16 Chiasma Inc. Octréotide destiné à être administré par voie orale en association avec d'autres agents thérapeutiques
WO2018060212A1 (fr) * 2016-09-27 2018-04-05 Camurus Ab Mélanges et préparations comportant un sel d'edta de type alkylammonium

Patent Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002356464A (ja) * 2001-05-30 2002-12-13 Showa Denko Kk 高純度アミノポリカルボン酸及びその塩と製造方法
WO2005014777A2 (fr) * 2002-10-16 2005-02-17 Board Of Regents, The University Of Texas System Procedes et compositions pour augmenter l'efficacite de substances actives d'un point de vue biologique
WO2005117830A1 (fr) 2004-06-04 2005-12-15 Camurus Ab Formulations de depot lipidique
WO2006075124A1 (fr) 2005-01-14 2006-07-20 Camurus Ab Formulations à base d'analogues de somatostatine
WO2006075123A1 (fr) 2005-01-14 2006-07-20 Camurus Ab Formulations bioadhesives topiques
WO2006075125A1 (fr) 2005-01-14 2006-07-20 Camurus Ab Formulations d'analogues de gnrh
WO2006131730A1 (fr) 2005-06-06 2006-12-14 Camurus Ab Formulations d'analogues de glp-1
WO2010020794A1 (fr) 2008-08-22 2010-02-25 Camurus Ab Préparations lipidiques comprenant un antioxydant thiolé
WO2012160213A1 (fr) 2011-05-25 2012-11-29 Camurus Ab Formulations peptidiques à libération contrôlée
WO2013083459A1 (fr) 2011-12-05 2013-06-13 Camurus Ab Formulations peptidiques robustes à libération contrôlée
WO2013083460A1 (fr) 2011-12-05 2013-06-13 Camurus Ab Formulations à libération contrôlée robustes
WO2013174978A1 (fr) * 2012-05-25 2013-11-28 Camurus Ab Formulation d'agoniste des récepteurs à la somatostatine
WO2014016428A1 (fr) 2012-07-26 2014-01-30 Camurus Ab Formulations d'opioïdes
WO2016066655A1 (fr) 2014-10-27 2016-05-06 Camurus Ab Formulation injectable de buprénorphine
WO2016102683A1 (fr) 2014-12-23 2016-06-30 Camurus Ab Formulations à libération contrôlée

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Section Ch Week 200314, Derwent World Patents Index; Class D25, AN 2003-143530, XP002776439, SAITO M; TANI T; UEDA T: "Highly pure aminopolycarboxylic acids of limited metal contents and their salts useful as processing agents for board surface of semiconductors" *
SCOTT; KYFFIN, BIOCHEM. J., vol. 169, 1978, pages 697 - 701

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10688148B2 (en) 2016-09-27 2020-06-23 Camurus Ab Formulations containing a somatostatin receptor agonist
US11135264B2 (en) 2016-09-27 2021-10-05 Camurus Ab Formulations containing a somatostatin receptor agonist
US11241476B2 (en) 2016-09-27 2022-02-08 Camurus Ab Mixtures and formulations comprising an alkyl ammonium EDTA salt
US11564968B2 (en) 2016-09-27 2023-01-31 Camurus Ab Formulations containing a somatostatin receptor agonist
WO2020240017A1 (fr) 2019-05-29 2020-12-03 Camurus Ab Compositions à libération contrôlée de lipides

Also Published As

Publication number Publication date
WO2018060213A1 (fr) 2018-04-05
CN109789215B (zh) 2022-12-16
TWI756270B (zh) 2022-03-01
RU2019110439A3 (fr) 2021-02-12
EP3518977A1 (fr) 2019-08-07
US20220257694A1 (en) 2022-08-18
IL295457A (en) 2022-10-01
EP3518978A1 (fr) 2019-08-07
TWI805558B (zh) 2023-06-21
US20220168381A1 (en) 2022-06-02
US20190262419A1 (en) 2019-08-29
MX2019003520A (es) 2019-11-11
US10688148B2 (en) 2020-06-23
IL265535B (en) 2022-09-01
RU2019110439A (ru) 2020-10-29
KR102611788B1 (ko) 2023-12-12
US20200138954A1 (en) 2020-05-07
AU2017336199A9 (en) 2019-05-23
JP7138626B2 (ja) 2022-09-16
TW201813631A (zh) 2018-04-16
CN109789214A (zh) 2019-05-21
CN109789214B (zh) 2022-06-28
IL265535A (en) 2019-05-30
TW201813662A (zh) 2018-04-16
CA3038412A1 (fr) 2018-04-05
CN109789215A (zh) 2019-05-21
US11135264B2 (en) 2021-10-05
KR20190084243A (ko) 2019-07-16
US20210008151A1 (en) 2021-01-14
US11564968B2 (en) 2023-01-31
JP2019529470A (ja) 2019-10-17
AU2017336199B2 (en) 2020-08-20
US11241476B2 (en) 2022-02-08
AU2017336199A1 (en) 2019-04-18

Similar Documents

Publication Publication Date Title
US20220257694A1 (en) Mixtures and formulations
EP2787975B1 (fr) Formulations à libération contrôlée robustes
US20200353086A1 (en) Controlled-release formulations
US20230285502A1 (en) Mixtures and formulations
RU2775780C2 (ru) Смеси и составы, содержащие алкиламмониевую соль эдта

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17772707

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 3038412

Country of ref document: CA

Ref document number: 2019516405

Country of ref document: JP

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 20197008819

Country of ref document: KR

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2017336199

Country of ref document: AU

Date of ref document: 20170926

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2017772707

Country of ref document: EP

Effective date: 20190429